No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Novel concepts in HDL pharmacology
Abstract
High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In
this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and
some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising
HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating
the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these
new HDL based therapies will also be discussed.
... Nicotinic acid, also known as niacin, is one of the group B vitamins. Supplementation with niacin increases HDLc via enhanced hepatic apoA-I production and inhibition of SR-B1-independent HDL-holoparticle uptake and catabolism in the liver [443,444]. Besides the significant increase in HDL and decrease in TAG levels that were clinically observed in patients, in many trials was the niacin therapy unsuccessful in decreasing CVD events [445,446]. ...
... Fibrates PPAR ligands, ↑apoA-I, ↑apoA-II → ↑HDL biogenesis, ↓apoC-III, ↑ABCA1/G1 and SR-B1 expression → ↑RCT some trials showed lack of efficacy, better effect was observed in the combination with statins, recent meta-analyses showed promising reduction in CVD risk in population with specific metabolic conditions [423] Niacin liver: ↑apoA-I, ↓HDL uptake, ↓HDL catabolism → ↑HDLc trials show lack of benefit in patients with CVD concomitantly treated with statins [443] Statins ↑PPARα → ↑ApoA-I mRNA, ↓CETP beneficial effect on CVD risk was confirmed in meta-analyses, effect on HDL is not the primary mechanism of statins' therapy, but it could contribute to its efficacy, observed raised incidence of DM, muscular side effects [452,463] Volanesorsen antisense oligonucleotid against ApoC-III mRNA → ↓apoC-III synthesis increase in plasmatic HDL and decrease in TAGs and non-HDL levels was observed in clinical trials [468] ApoC-III mRNA, which prevents the synthesis of apoC-III protein as a treatment for familial chylomicronaemia syndrome [465]. Since some studies suggest that apoC-III-bound lipoproteins have altered metabolism and apoC-III is involved in many pro-atherogenic processes, inhibition of the synthesis could have protective activity [466]. ...
... ApoJ mimetic peptides ↑RCT, ↓lipoprotein lipid peroxides, ↑PON1, improved anti-inflammatory HDL function Mice, monkeys [594,595] ApoC-II mimetic peptides ↑ABCA1-mediated cholesterol efflux mice [596,597] Antisense oligonucleotides altering expression of specific genes (CETP) mice [598] inhibiting miRNAs involved in HDL metabolism and function (miR-33 a/b) primate, mice [599,600] SR-B1 inhibitors ↓SR-B1-mediated uptake of HDL to liver → ↑HDLc Humans, mice [443,601] Hydrogen-rich water ↓Lp-PLA2, ↑LCAT, antioxidant activity (↑PON1) → improved HDL function, ↑CEC humans, rats, hamsters [603,604] Purified sardine proteins ↑LCAT → ↑RCT, ↑PON1 → ↓HDL oxidation rats [605,606] Photodynamic therapy with photosensitisers ↑ABCA1-mediated cholesterol eflux rabbits, mice [610,611] ...
Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis is chronic systemic low-grade inflammation triggering changes in lipoprotein structure and metabolism. HDL, an independent marker of cardiovascular risk, is a lipoprotein particle with numerous important anti-atherogenic properties. Besides the essential role in reverse cholesterol transport, HDL possesses antioxidative, anti-inflammatory, antiapoptotic, and antithrombotic properties. Inflammation and inflammation-associated pathologies can cause modifications in HDL’s proteome and lipidome, transforming HDL from atheroprotective into a pro-atherosclerotic lipoprotein. Therefore, a simple increase in HDL concentration in patients with inflammatory diseases has not led to the desired anti-atherogenic outcome. In this review, the functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail. Alterations of HDL proteome (such as replacing atheroprotective proteins by pro-inflammatory proteins, or posttranslational modifications) in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed. Finally, molecular, and clinical aspects of HDL-targeted therapies, including those used in therapeutical practice, drugs in clinical trials, and experimental drugs are comprehensively summarised.
... In WHHL rabbits, infusion of apolipoprotein A-I mimetic peptide/phospholipid complexes inhibited the progression of atherosclerosis mainly due to changes in LDL charge and by converting small, dense LDL into large, buoyant LDL (Iwata et al., 2011). According to our knowledge, the effects of other apolipoprotein A-I mimetic peptides, 6F and 5A, as well as an apolipoprotein E-derived HDL mimetic peptide, ATI-5261 were only investigated in animals lacking CETP (Balder et al., 2013;Remaley et al., 2014). ...
... In the ASSURE trial, RVX-208 failed to reduce atheroma volume in statin-treated patients (Remaley et al., 2014). ...
... Phase II trials investigating the effects of reconstituted HDL and apolipoprotein A-I mimetic peptide infusions (CSL-112, CER-001, APL-180 (L-4F)) are ongoing (clinicaltrials.gov). Other apolipoprotein mimetic peptides, 5A, 6F and ATI-5261 are currently in preclinical development (Balder et al., 2013;Remaley et al., 2014). Another infusion therapy with recombinant human lecithin cholesterol acyltransferase (LCAT), ACP-501 recently passed a phase I trial (clinical trials.gov) ...
... In WHHL rabbits, infusion of apolipoprotein A-I mimetic peptide/phospholipid complexes inhibited the progression of atherosclerosis mainly due to changes in LDL charge and by converting small, dense LDL into large, buoyant LDL (Iwata et al., 2011). According to our knowledge, the effects of other apolipoprotein A-I mimetic peptides, 6F and 5A, as well as an apolipoprotein E-derived HDL mimetic peptide, ATI-5261 were only investigated in animals lacking CETP (Balder et al., 2013;Remaley et al., 2014). ...
... In the ASSURE trial, RVX-208 failed to reduce atheroma volume in statin-treated patients (Remaley et al., 2014). ...
... Phase II trials investigating the effects of reconstituted HDL and apolipoprotein A-I mimetic peptide infusions (CSL-112, CER-001, APL-180 (L-4F)) are ongoing (clinicaltrials.gov). Other apolipoprotein mimetic peptides, 5A, 6F and ATI-5261 are currently in preclinical development (Balder et al., 2013;Remaley et al., 2014). Another infusion therapy with recombinant human lecithin cholesterol acyltransferase (LCAT), ACP-501 recently passed a phase I trial (clinical trials.gov) ...
... Increasing high-density lipoprotein cholesterol levels for cardiovascular benefit: The end of a dream? Angela Pirillo 1,2 and Alberico Luigi Catapano 2,3 For many decades, epidemiological studies have supported an inverse relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of cardiovascular disease. 1 This led to focus the efforts not only on the development of lipid-lowering drugs (first of all statins), but also on the development of drugs able to increase HDL-C levels. 2 Among these drugs, fibrates, niacin and cholesteryl ester transfer protein (CETP) inhibitors have played a major role. Despite the observations arising from epidemiological studies, interventional trials with HDL-C-raising drugs have generally failed to demonstrate a beneficial effect on cardiovascular outcomes. ...
... Angela Pirillo 1,2 and Alberico Luigi Catapano 2,3 For many decades, epidemiological studies have supported an inverse relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of cardiovascular disease. 1 This led to focus the efforts not only on the development of lipid-lowering drugs (first of all statins), but also on the development of drugs able to increase HDL-C levels. 2 Among these drugs, fibrates, niacin and cholesteryl ester transfer protein (CETP) inhibitors have played a major role. Despite the observations arising from epidemiological studies, interventional trials with HDL-C-raising drugs have generally failed to demonstrate a beneficial effect on cardiovascular outcomes. ...
... GPR109A binds the SCFA butyrate but also the tryptophan metabolite nicotinic acid. Nicotinic acid is currently used in metabolic diseases to decrease plasma TG and increase HDL-C levels (Remaley et al., 2014). All of the metabolite-sensing GPCRs are expressed by immune cells, particularly by innate-type cells . ...
... This is achieved mainly through the induction of the expression of the ATP-binding cassette (ABC) transporters, which mediate the reverse cholesterol transport to the liver (Tall and Yvan-Charvet, 2015). Importantly, cholesterol serves as an essential component of the membranes and is critical for the formation of lipid rafts, membrane microdomains that promote the assembly of signaling receptors (Catapano et al., 2014). Thus, cholesterol removal from cells might alter the formation of lipid rafts and the organization or signaling of TLRs and other immune receptors (Koseki et al., 2007). ...
The immune response requires major changes to metabolic processes, and indeed, energy metabolism and functional activation are fully integrated in immune cells to determine their ability to divide, differentiate, and carry out effector functions. Immune cell metabolism has therefore become an attractive target area for therapeutic purposes. A neglected aspect in the translation of immunometabolism is the critical connection between systemic and cellular metabolism. Here, we discuss the importance of understanding and manipulating the integration of systemic and immune cell metabolism through in-depth analysis of immune cell phenotype and function in human metabolic diseases and, in parallel, of the effects of conventional metabolic drugs on immune cell differentiation and function. We examine how the recent identification of selective metabolic programs operating in distinct immune cell subsets and functions has the potential to deliver tools for cell- and function-specific immunometabolic targeting.
... Nevertheless, drugs that raise HDL-C concentrations, cholesteryl ester transfer protein (CETP) inhibitors, are in late stage clinical development, and other approaches that enhance HDL function, such as reverse cholesterol transport, are in early stage clinical development. Remaley et al. briefly discussed the currently established the two main classes of drugs that raise HDL-C is nicotinic acid and fibrates [93]. Nicotinic acid is more effective in raising HDL-C, whereas fibrates are more effective in decreasing elevated triglyceride (TG) levels, which are often inversely associated with HDL levels. ...
... Recent advances in cell scaffolds provide a platform for delivery of bioactive molecules as well as a physical environment to allow for cell attachment thus preventing cells from being carried away. A variety of materials have been used as cell scaffolds including synthetic and natural polymers and hydrogels, native extracellular matrix (ECM) proteins, and processed native ECM following myocardial infarction towards cardiovascular tissue regeneration [93]. Moreover, in recent years, more advances in methods of stem cell isolation, culture in bioreactors, and the synthesis of bioactive materials promise to create engineered tissue ex vivo. ...
Cardiovascular disease (CVD), accounting around 30% of deaths worldwide, collectively comprised of disorders affecting the heart and blood vessels as well as their associated adverse conditions. Despite outstanding progress in the area of the treatments of CVDs, significant challenges remain in designing of efficient delivery systems for myocardial therapy. Moreover, current therapy for CVDs is limited due to various clinical complications such as systemic toxicity, stent thrombosis, etc. Molecular and nanotechnology approaches provide the tools to explore such frontiers of biomedical science at the cellular level and thus offer unique features for potential application in the field of cardiac therapy. In this review, recent advances in CVD related risk factors, chronic inflammation, and their therapeutic modalities such as stem cell therapy, gene delivery, tissue factor (TF) inhibitors, miRNAs, leukotriene modifiers, thrombolytic agents etc., in modern molecular aspects are discussed. Moreover, nanoparticle based drug delivery, nanocarriers as molecular imaging, and the various challenges of myocardial tissue engineering aspects have been summarized. All these aspects may provide additional therapeutic substitutes in clinical trials for the registration of new drugs.
... 12 CETP is also required for cholesterol uptake from LDL through the RCT pathway. 100 Dalcetrapib (JTT-705) was the first functional CETP inhibitor. 101 This agent caused a 34% increase in HDL-C. ...
Introduction
Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High‐density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti‐diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins.
Methods
This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM.
Results
The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non‐insulin‐dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti‐oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low‐density lipoprotein, which facilitate insulin secretion.
Conclusion
Therefore, HDL and its compositions, especially Apo A‐I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A‐I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.
... De plus,ITX5061 a induit une régression des lésions précoces dans l'arc aortique (-40% de la taille des lésions) dans un modèle murin d'athérosclérose, les souris LDLR +/sous un régime athérogène. A ce jour, l'effet de cet inhibiteur sur le développement de l'athérosclérose chez l'homme n'a pas été évalué.Cependant l'effet bénéfique de l'inhibition de SR-BI qui participe à la captation hépatique des HDL et à l'efflux de cholestérol cellulaire est questionnable, puisque ceci entraînerait possiblement une altération du RCT chez l'homme(Masson et al., 2009) (Remaley, Norata, & Catapano, 2014). La protéine adaptatrice PDZK1, qui régule notamment l'expression protéique de SR-BI au niveau hépatique permettant ainsi une régulation tissu-spécifique de la fonction de SR-BI dans la captation séléctive du cholestérol estérifié pourrait constituer une cible thérapeutique intéressante dans la prévention et le traitement des maladies cardiovasculaires. ...
L’effet athéroprotecteur des Lipoprotéines de Haute Densité (HDL) est principalement attribué à leur rôle clé dans Transport Retour du Cholestérol (RCT), un processus par lequel le cholestérol excédentaire des cellules périphériques est capté par les particules HDL pour être amené au foie où il sera préférentiellement sécrété dans les voies biliaires, puis excrété dans les fèces. Deux voies indépendantes ont été identifiées comme étant impliquées dans l’endocytose hépatique du HDL. La première est la voie ecto-F1-ATPase/P2Y13 dans laquelle l’apoA-I (apolipoprotéine majoritaire des HDL) se lie à la F1-ATPase exprimé à la surface des hépatocytes (ecto-F1-ATPase) et stimule l’hydrolyse d’ATP en ADP. L’ADP ainsi généré active le récepteur purinergique P2Y13 pour stimuler l’endocytose de l’holoparticule HDL (protéines + lipides) via un troisième récepteur différent de SR-BI. Les souris invalidées pour P2Y13 présentent une diminution des sécrétions de lipides biliaires accompagnée d’une diminution du RCT des macrophages vers les fèces sous régime normolipidique. Un régime riche en cholestérol (1.25% cholestérol) accentue ce phénotype. La voie SR-BI, quant à elle, est responsable de la captation sélective du cholestérol estérifié des HDL par le foie. Les souris invalidées pour SR-BI spécifiquement au niveau du foie (SR-BI KOfoie) présentent une hypercholestérolémie principalement attribuée à une augmentation du HDL-C et développent des plaques d’athérosclérose sous régime hypercholestérolémique. Dans une étude récente, nous avons montré que l’invalidation de P2Y13 dans le modèle murin proathérogène apoE KO induit une augmentation du développement d’athérosclérose associée à une diminution des sécrétions de lipides biliaires et du RCT des macrophages vers les fèces. De plus, dans ces souris, l’expression hépatique transcriptionnelle et protéique de SR-BI étaient fortement augmentées par rapport aux souris apoE KO, suggérant qu’un possible mécanisme de compensation pourrait exister entre les récepteurs P2Y13 et SR-BI. L’objectif de ma thèse a été d’étudier la contribution respective des récepteur P2Y13 et SR-BI dans le métabolisme du HDL-C et le développement de l’athérosclérose. Nous avons croisé des souris P2Y13 KO avec des souris SR-BI KOfoie et nous avons obtenu des souris doublement invalidées (P2Y13 x SR-BIfoie dKO). Le phénotype métabolique des souris dKO a été étudié sous régime normolipidique et hypercholestérolémique et le développement d’athérosclérose sous régime hypercholestérolémique. Par rapport aux souris sauvages, les souris dKO sous régime normolipidique, présentent une augmentation du cholestérol plasmatique similaire à celle observée chez les souris SR-BI KOfoie, principalement imputable à une augmentation du HDL-C. Les souris dKO, mais pas les souris SR-BI KO, montrent une diminution des sécrétions de lipides biliaires comparable à celle observée chez les souris P2Y13 KO. Ce phénotype métabolique observé chez les souris dKO est accentué sous régime hypercholestérolémique et est associé à une augmentation des plaques d’athérosclérose par rapport aux souris SR-BI KOfoie. L’ensemble des résultats montrent que la délétion hépatique de SR-BI contribue essentiellement à une augmentation des taux plasmatiques de cholestérol, et plus particulièrement HDL-C. La délétion de P2Y13, quant à elle, n’induit aucune variation des lipides plasmatiques mais contribue principalement à une diminution des sécrétions de lipides biliaires qui contribue au développement de l’athérosclérose chez les souris invalidées pour SR-BI hépatique. Ces résultats soutiennent le concept selon lequel le flux de cholestérol transporté par les HDL des tissus périphériques vers le foie et les voies de sécrétions biliaires est plus important dans l’athéro-protection que la concentration plasmatique en HDL-C. L’activation du récepteur P2Y13 constitue une approche thérapeutique intéressante pour cibler les HDL contre le développement de l’athérosclérose.
... Nascent discoidal HDL particles transport cholesterol from tissues to the liver, a process termed reverse cholesterol transport (6). Although reverse cholesterol efflux was thought to be solely responsible for the cardiovascular protective effects of HDL, the ability to attenuate endothelial dysfunction may be equally important (7)(8)(9)(10). HDL is associated with numerous proteins and lipids that endow it with cytoprotective and anti-inflammatory properties (11,12). ...
High-density lipoprotein (HDL) particles suppress inflammation-induced tissue injury via vascular and myeloid cell-dependent mechanisms. As such, HDL-associated bioactive lipids such as sphingosine 1-phosphate (S1P) and prostacyclin (PGI2) signal via their respective G protein-coupled receptors on target cells to promote vascular endothelial function and suppress platelet and myeloid-dependent pathophysiology. Here we have constructed a fusion protein of apolipoprotein A1 (ApoA1) and apolipoprotein M (ApoM) (A1M) that forms HDL-like particles and chaperones S1P and Iloprost, stable PGI2 analog. A1M/S1P complex activates S1P receptor-1 (S1PR1) as a Gαi-biased agonist and attenuates the inflammation-induced NFκB pathway while A1M/Iloprost acts via IP receptor to inhibit platelet aggregation and promote endothelial barrier function. In addition to enhancing the endothelial barrier, A1M/S1P suppresses neutrophil influx, oxidative burst and inflammatory mediator secretion in a sterile inflammation model. We propose that A1M could be useful as a therapeutic to induce S1P and PGI2-dependent anti-inflammatory functions and suppress collateral tissue injury.
... MSPs are derivatives of the human ApoA1 protein 8 that itself forms discoidal high-density lipoprotein particles in the body. 9 The size of the nanodisc not only scales with the length of the surrounding MSP belt 10 but is also affected by the lipid loading. 11 MSP-based nanodiscs have been successfully employed to investigate the structure and function of different membrane proteins. ...
... It did inhibit inflammation; however, plasma lipid profile was not affected by it [76]. An intravenous infusion of L4F (containing L-form amino acids only) in a similar study had no effect whatsoever [77]. ...
Apo-A1 is correlated with conditions like hyperlipidemia, cardiovascular diseases, high altitude pulmonary edema and etc. where hypoxia constitutes an important facet.Hypoxia causes oxidative stress, vaso-destructive and inflammatory outcomes.Apo-A1 is reported to have vasoprotective, anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, effects of Apo-A1 augmentation during hypoxia exposure are unknown.In this study, we investigated the effects of exogenously supplementing Apo-A1-mimetic peptide on SD rats during hypoxia exposure. For easing the processes of delivery, absorption and bio-availability, Apo-A1 mimetic peptide D4F was used. The rats were given 10 mg/kg BW dose (i.p.) of D4F for 7 days and then exposed to hypoxia. D4F was observed to attenuate both oxidative stress and inflammation during hypoxic exposure. D4F improved energy homeostasis during hypoxic exposure. D4F did not affect HIF-1a levels during hypoxia but increased MnSOD levels while decreasing CRP and Apo-B levels. D4F showed promise as a prophylactic against hypoxia exposure.
... At least in animals, numerous studies have demonstrated that HDL exerts a protective effect on the development of atherosclerosis through a wide range of mechanisms, such as reverse cholesterol transport and anti-inflammatory properties. [29] Our in vitro cholesterol efflux assay revealed that dietary palmitoleate, but not olive oil, improved cholesterol efflux capacity by ABCA1, an ATP-binding cassette transporter that promotes cellular phospholipid and cholesterol efflux. [30] Furthermore, the favorable impact of dietary palmitoleate on HDL observed in the present study is in agreement with previous studies in rodents and human subjects. ...
Scope:
Palmitoleic acid (palmitoleate; C16:1 n-7), an omega-7 monounsaturated fatty acid (MUFA) found in plants and marine sources, has been shown to favorably modulate lipid and glucose metabolism. Its impact, however, on atherosclerosis has not been examined in detail.
Methods and results:
LDL receptor knock-out (LDLR-KO) mice were fed a Western diet supplemented with 5% (w/w) palmitoleate concentrate, oleic-rich olive oil, or none (control) for 12 weeks. Dietary palmitoleate increased hepatic C16:1 levels, improved plasma and hepatic lipid/lipoprotein profiles (∼40% decrease in triglycerides), and reduced the atherosclerotic plaque area by ∼45% compared with control or olive oil group (p<0.05). These favorable changes were accompanied by the down-regulation of key genes, such as Srebp1c, Scd1, Il-1β, and Tnfα. ApoB-depleted plasma from mice fed palmitoleate had increased cholesterol efflux capacity by 20% from ABCA1-expressing cells (p<0.05). We further observed a beneficial effect of palmitoleate on glucose metabolism (54% decreased in HOMA-IR, p<0.05).
Conclusions:
Dietary supplemented palmitoleate reduces atherosclerosis development in LDLR-KO mice, and was associated with improvement of lipid and glucose metabolism and favorable changes in regulatory genes involved in lipogenesis and inflammation. These findings imply the potential role of dietary palmitoleate in the prevention of cardiovascular disease and diet-induced metabolic disorders. This article is protected by copyright. All rights reserved.
... Hypertriglyceridemia is due to reduced plasma Triglyceride (TG) clearance rate [16]. An increase in triglyceride levels during sepsis might have beneficial effects on the host because triglyceriderich lipoproteins bind and neutralize the effects of endotoxin [19]. The hypocholesterolemia of acute illness is associated with a moderate increase in triacylglyceride levels [20]. ...
... The ratio of LDL and HDL can be used as indicator for people with high risk of cardiovascular diseases (Acay et al. 2014) due to LDL can be oxidized which will increase the risk of atherosclerosis (Rohatgi et al. 2014). The way to decrease lipid profiles in the body was by taking medications such as statins, triparanol, resins, torcetrapib, probucol, and niacin (Remaley et al. 2014). One of the negative of these medications is they can be harmful for the human body. ...
Background: people commonly consume some seeds like steeping as beverage. This is the first study that was to prove the effects of anti-atherogenic properties of beverage of the date seeds in pre-menopause women. Materials and methods: The quasi-experimental design was used in the study. Thirty-two of pre-menopause women with hyperlipidemia history in Gununglurah village, Banyumas, Central Java were recruited. Each participant signed an informed consent to obtain a 5 cc blood sample through the mediana cubital vein. Lipid profiles test was done before and after treatment. Beverage of the Date seeds of Deglet Nour cultivar was consumed for 14 days with the dosage of 2.5 grams each day. The data were analyzed by using the paired t-test with a significance level of p< 0.05. Results: Prior to treatment, pre-menopause women tend to have unhealthy lipid profile. The mean scores of total cholesterol, triglyceride, HDL and LDL levels were 251.53 35.23, 232.50 35.17, 35.69 6.55, 167.11 40.31 mg/dL respectively. After consuming beverage of the date seeds, the total cholesterol, triglycerides, LDL, and atherogenic levels were decreased, while HDL level was significantly increased (p< 0.05). Conclusion: The study demonstrated that the lipid profiles of the pre-menopause women were improved after date seed beverage consumption. The implication of the study was that pre-menopause women could consume the date seed beverage routinely to maintain a good lipid profiles and keep healthy. The professional health care also can give the education regarding with the benefit of the date seed beverage in decreasing the lipid profiles in pre-menopause women.
... The atheroprotective role of HDL is related to their key function in reverse cholesterol transport (RCT), as well as a number of additional potentially favorable properties including anti-inflammatory, antithrombotic, and antioxidant effects ( Fig. 1) [2]. Accordingly, several efforts to de-velop drugs to increase HDL-C levels have been undertaken [3]. These approaches, including those aimed at increasing apolipoprotein A-I (apoA-I) levels, have shown some beneficial effects either in preclinical studies [4][5][6] or in patients with coronary heart disease (CHD) [7][8][9][10]. ...
Epidemiological studies have suggested an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology.
The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as “dysfunctional” HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. The aim of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond.
... Although we observed a small, but not significant, increase of HDLC after AT protocol, it is important to note that in the CG there was a reduction in the concentration of this biomarker. Considering that HDLC plasma concentration can be increased by the use of medications, primarily statin [25] and lately nicotinic acid and fibrates [26], and maybe AT could be a nonpharmacological treatment that promotes this fact. On the other hand, the alterations in these biomarkers are interesting because reduction of anthropometric factors of these obese patients after treatment protocol was not observed. ...
Knee osteoarthritis (KOA) is one of the most frequent non-communicable diseases with pain associated symptoms and affects the musculoskeletal system. Various forms of treatment can be indicated and non-pharmacological treatment is also an available option for the management of KOA individuals. For instance, auriculotherapy (AT) is one possible procedure associated with the Traditional Chinese Medicine for dealing with KOA. It is believed that the concentration of certain biomarkers could be altered in individuals with KOA after AT. The aim of this study was to evaluate the effect of AT on plasma concentration of biomarkers in KOA individuals. This intervention is a controlled trial. Twenty-one subjects were grouped in two groups and (i) submitted to AT with the stimulation of the Shen Men points, kidney and knee in the treatment group, or (ii) different points in the control group, once a week for five weeks. Blood was collected before the beginning of protocols and a week after the last session. Kolmogorov-Smirnov and Wilcoxon tests were performed and P value ≤0.05 was considered statistically significant. Hematological parameters did not show any significant variation between the control group and treated group. Concerning the biochemical parameters, a significant reduction of direct bilirubin (from 43.31±22.10 to 21.21±5.30μmol/L, p=0.003), aspartate aminotransferase (from 0.48±0.16 to 0.38±0.09μKat/L, p=0.010) and triglycerides (from 7.04±2.90 to 5.45±2.57mmol/L, p=0.008) in the treated group was obtained. In conclusion, the analysis of results suggests that AT might be a useful intervention for the management of KOA individuals.
... Lipid nanodiscs are planar assemblies consisting of a lipid bilayer stabilized by protein, peptide, or polymer scaffolds. Naturally occurring nanodiscs such as nascent high-density lipoprotein are cardio-protective and play a critical role in reverse cholesterol transport (RCT) [1,2]. RCT begins when APOA1 interacts with the ATP-binding cassette subfamily A member 1 (ABCA1), which transports lipids and cholesterols from macrophages, a process called cholesterol efflux. ...
A lipid nanodisc is a discoidal lipid bilayer stabilized by proteins, peptides, or polymers on its edge. Nanodiscs have two important connections to structural biology. The first is associated with high-density lipoprotein (HDL), a particle with a variety of functionalities including lipid transport. Nascent HDL (nHDL) is a nanodisc stabilized by Apolipoprotein A-I (APOA1). Determining the structure of APOA1 and its mimetic peptides in nanodiscs is crucial to understanding pathologies related to HDL maturation and designing effective therapies. Secondly, nanodiscs offer non-detergent membrane-mimicking environments and greatly facilitate structural studies of membrane proteins. Although seemingly similar, natural and synthetic nanodiscs are different in that nHDL is heterogeneous in size, due to APOA1 elasticity, and gradually matures to become spherical. Synthetic nanodiscs, in contrast, should be homogenous, stable, and size-tunable. This report reviews previous molecular dynamics (MD) simulation studies of nanodiscs and illustrates convergence and accuracy issues using results from new multi-microsecond atomistic MD simulations. These new simulations reveal that APOA1 helices take 10-20 μs to rearrange on the nanodisc, while peptides take 2 μs to migrate from the disc surfaces to the edge. These systems can also become kinetically trapped depending on the initial conditions. For example, APOA1 was trapped in a biologically irrelevant conformation for the duration of a 10 μs trajectory; the peptides were similarly trapped for 5 μs. It therefore remains essential to validate MD simulations of these systems with experiments due to convergence and accuracy issues. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo.
... Studies have established the association of low plasma HDL cholesterol concentration with an elevated risk of cardiovascular diseases (2), and more recently, the importance of HDL particle size in the plasma (3,4). The atheroprotective property of HDL is attributed to its role in a multistep process called reverse cholesterol transport (RCT) (5). RCT starts when APOA1 interacts with the ATP-binding cassette subfamily A member 1 (ABCA1). ...
Significance
High-density lipoprotein (HDL), popularly known as “good cholesterol,” is an assembly of lipids and proteins that is protective against cardiovascular diseases. HDL begins to develop when two copies of the protein apolipoprotein A-I (APOA1) mediate the removal of excess lipids from peripheral cells and form a nanodisc. How the proteins adjust their structures as the nanodisc increases in diameter, mediates the conversion of cholesterol to cholesteryl esters, and becomes spherical is crucial to understanding HDL maturation and relevant pathologies. This study combines multimicrosecond atomistic molecular dynamics simulations, molecular modeling, and cross-linking experiments to reveal APOA1 structure in two nascent HDLs. The structures provide a mechanistic understanding for HDL maturation and revise previous models of nascent HDL.
... HDL is often known as "good" cholesterol. As higher plasma levels of HDL cholesterol are usually associated with a lower risk of atherosclerosis (AS) [2], HDL-modulating interventions currently undergoing development may reduce cardiovascular risk [3][4][5]. However, recent clinical and genetic studies suggest that the blood level of HDL cholesterol itself is not a sufficient therapeutic target in AS diseases such as coronary artery disease [6,7]. 1 3 In this context, effects of HDL on vascular biology have also attracted enormous attention as potential therapeutic targets in prevention and treatment of AS diseases (e.g., coronary heart disease and stroke) [2]. ...
High-density lipoprotein (HDL) has previously been shown to promote angiogenesis. However, the mechanisms by which HDL enhances the formation of blood vessels remain to be defined. To address this, the effects of HDL on the proliferation, transwell migration and tube formation of human umbilical vein endothelial cells were investigated. By examining the abundance and phosphorylation (i.e., activation) of the vascular endothelial growth factor receptor VEGFR2 and modulating the activity of the sphingosine-1 phosphate receptors S1P1–3 and VEGFR2, we characterized mechanisms controlling angiogenic responses in response to HDL exposure. Here, we report that HDL dose-dependently increased endothelial proliferation, migration and tube formation. These events were in association with increased VEGFR2 abundance and rapid VEGFR2 phosphorylation at Tyr1054/Tyr1059 and Tyr1175 residues in response to HDL. Blockade of VEGFR2 activation by the VEGFR2 inhibitor SU1498 markedly abrogated the pro-angiogenic capacity of HDL. Moreover, the S1P3 inhibitor suramin prevented VEGFR2 expression and abolished endothelial migration and tube formation, while the S1P1 agonist CYM-5442 and the S1P2 inhibitor JTE-013 had no effect. Last, the role of S1P3 was further confirmed in regulation of S1P-induced endothelial proliferation, migration and tube formation via up-regulation and activation of VEGFR2. Together, these findings argue that HDL promotes angiogenesis via S1P3-dependent up-regulation and activation of VEGFR2 and also suggest that the S1P–S1P3–VEGFR2 signaling cascades as a novel target for HDL-modulating therapy implicated in vascular remodeling and functional recovery in atherosclerotic diseases such as myocardial infarction and ischemic stroke.
... In those reviews, images illustrate HDL metabolism in insulin resistance with metabolic disease, 26 HDL influence on endothelial function in coronary artery disease, 27 and novel concepts in HDL pharmacology (reverse cholesterol transport). 28 The take-off of the PCSK9 inhibitors has sparked a lot of attention and a cutting edge review is presented by Norata et al. 29 ...
... We recently developed recombinant human LCAT (rhLCAT) as a potential therapy and showed that it safely increased HDL-C levels in both CAD and FLD patients (Shamburek et al., 2016a;Shamburek et al., 2016b). Because rhLCAT raises HDL and enhances cholesterol efflux, it might protect against CVD, particularly acute coronary syndrome, similar to findings with reconstituted HDL in early-stage clinical trials (Krause and Remaley, 2013;Remaley et al., 2008;Remaley et al., 2014). rhLCAT therapy, however, will likely be relatively expensive and require intravenous infusion. ...
Background:
Lecithin:cholesterol acyltransferase (LCAT) catalyzes plasma cholesteryl ester formation and is defective in Familial LCAT Deficiency (FLD), an autosomal recessive disorder characterized by low HDL, anemia and renal disease.
Objective:
To investigate the mechanism by which Compound A, a small heterocyclic amine, activates LCAT.
Methods:
Effect of Compound A on LCAT was tested in human plasma and with recombinant LCAT. Mass spectrometry and NMR was used to determine Compound A adduct formation with LCAT. Molecular modeling was performed to gain insight into Compound A effects on LCAT structure and activity.
Results:
Compound A increased LCAT activity in a subset (3 out of 9) of LCAT mutations to levels comparable to FLD heterozygotes. The site-directed mutation LCAT-Cys31Gly prevented activation by Compound A. Substitution of Cys31 with charged residues (Glu, Arg and Lys) decreased LCAT activity, whereas bulky hydrophobic groups (Trp, Leu, Phe and Met) increased activity up to 3-fold (p<0.005). Mass spectrometry of a tryptic digest of LCAT incubated with Compound A revealed a +103.017 m/z adduct on Cys31, consistent with addition of a single hydrophobic cyanopyrazine ring. Molecular modeling identified potential interactions of Compound A near Cys31 and structural changes correlating with enhanced activity. Functional groups important for LCAT activation by Compound A were identified by testing Compound A derivatives. Finally, sulfhydryl-reactive β-lactams were developed as a new class of LCAT activators.
Conclusions:
Compound A activates LCAT, including some FLD mutations, by forming a hydrophobic adduct with Cys31, thus providing a mechanistic rationale for the design of future LCAT activators.
... 8 Due to the function of CETP and the association of the gene with HDL-C in humans, 9,10 the CETP gene is one of the targets for drug development for dyslipidemia. 6,11,12 CETP-inhibition leads to an increase of HDL-C from 30 up to 140% depending on the compound used. The first drug of its class, Torcetrapib was unfortunately associated with an increased mortality and morbidity in patients receiving the CETP inhibitor in addition to atorvastatin. ...
Background
Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.
Methods
We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.
Results
The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10⁻⁵⁰⁹), βadjusted=0.859 mg/dl (P value=9.51×10⁻²⁵)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.
Conclusions
The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.
... Administration of reconstituted HDL, HDL mimetics and apolipoprotein A-I peptides has been one of the many approaches to raise HDL in attempt to treat cardiovascular disease (Kingwell et al., 2014). Several potentially beneficial effects have been observed in experimental models of disease and encouraging results reported for some of these preparations, respectively, e.g., in acute coronary syndrome where atherosclerotic plaque volume was reduced and inflammation ameliorated (Reddy et al., 2014;Remaley et al., 2014;White et al., 2014). Interestingly, among the functional effects caused by HDL administration are several that have been attributed at least in part to HDL-S1P such as arterial vasodilation. ...
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid contained in High-density lipoproteins (HDL) and has drawn considerable attention in the lipoprotein field as numerous studies have demonstrated its contribution to several functions inherent to HDL. Some of them are partly and some entirely due to the S1P contained in HDL (HDL-S1P). Despite the presence of over 1000 different lipids in HDL, S1P stands out as it possesses its own cell surface receptors through which it exercises key physiological functions. Most of the S1P in human plasma is associated with HDL, and the amount of HDL-S1P influences the quality and quantity of HDL-dependent functions. The main binding partner of S1P in HDL is apolipoprotein M but others may also exist particularly under conditions of acute S1P elevations. HDL not only exercise functions through their S1P content but have also an impact on genuine S1P signaling by influencing S1P bioactivity and receptor presentation. HDL-S1P content is altered in human diseases such as atherosclerosis, coronary artery disease, myocardial infarction, renal insufficiency and diabetes mellitus. Low HDL-S1P has also been linked to impaired HDL functions associated with these disorders. Although the pathophysiological and molecular reasons for such disease-associated shifts in HDL-S1P are little understood, there have been successful approaches to circumvent their adverse implications by pharmacologically increasing HDL-S1P as means to improve HDL function. This mini-review will cover the current understanding of the contribution of HDL-S1P to physiological HDL function, its alteration in disease and ways for its restoration to correct HDL dysfunction.
... However, a recent genetic analysis failed to show a causal association between genetically raised plasma HDL cholesterol levels and risk for myocardial infarction [5]. In addition, nicotinic acid and fibrates currently are used to increase HDL-C levels, both of which have some weaknesses (e.g., uricosuria, increased glucose tolerance and flushing for nicotinic acid and problematic pharmacokinetic interactions for fibrates) that impose restrictions on their use [6]. Moreover, raising HDL-cholesterol by the cholesteryl-ester transfer protein (CETP) inhibitor did not play its expected role in protection from CVD [7,8]. ...
The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C-raising drugs show no clear association with risks for CVD. At the genetic level, recent research indicates that steady-state HDL-C concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. It is evident that the newer strategies may replace therapeutic approaches to simply raise plasma HDL-C levels. There is an urgent need to identify an efficient biomarker that accurately predicts the increased risk of atherosclerosis (AS) in patients and that may be used for exploring newer therapeutic targets. Studies from recent decades show that the composition, structure and function of circulating HDL are closely associated with high cardiovascular risk. A vast amount of data demonstrates that the most important mechanism through which HDL antagonizes AS involves the reverse cholesterol transport (RCT) process. Clinical trials of drugs that specifically target HDL have so far proven disappointing, so it is necessary to carry out review on the HDL therapeutics.
... Some other drugs have been developed to treat dyslipidemia in specific subsets of patients. For instance, fibrates, which bind to the nuclear receptor PPAR-alpha, can increase HDL levels and decrease triglyceride levels [27]. Fibrates were originally used to address the primary problem of high levels of triglycerides. ...
Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios.
... The atheroprotective role of HDL is related to their key function in reverse cholesterol transport (RCT), as well as a number of additional potentially favorable properties including anti-inflammatory, antithrombotic, and antioxidant ef- fects ( Fig. 1) [2]. Accordingly, several efforts to de-velop drugs to increase HDL-C levels have been under- taken [3]. These approaches, including those aimed at increasing apolipoprotein A-I (apoA-I) levels, have shown some beneficial effects either in preclinical studies [4][5][6] or in patients with coronary heart disease (CHD) [7][8][9][10]. ...
Epidemiological and clinical studies have demonstrated the inverse association between HDL cholesterol levels (HDL-C) and the risk of coronary heart disease (CHD). This correlation is believed to relate to the ability of HDL to promote reverse cholesterol transport. Remodeling of HDL due to chemical/physical modifications can dramatically affect its functions, leading to dysfunctional HDL that could promote atherogenesis. HDL modification can be achieved by different means: (i) non-enzymatic modifications, owing to the presence of free metal ions in the atherosclerotic plaques; (ii) cell-associated enzymes, which can degrade the apoproteins without significant changes in the lipid moiety, or can alternatively induce apoprotein cross-linking and lipid oxidation; (iii) association with acute phase proteins, whose circulating levels are significantly increased during inflammation which may modify HDL structure and functions; and (iv) metabolic modifications, such as glycation that occurs under hyperglycaemic conditions. Available data suggest that HDL can easily be modified losing their anti-atherogenic activities. These observation results mainly from in vitro studies, while few in vivo data, are available. Furthermore the in vivo mechanisms involved in HDL modification are ill understood. A better knowledge of these pathways may provide possible therapeutic target aimed at reducing HDL modification.
High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.
El Virus de inmunodeficiencia humana (VIH) ha sido objeto de estudios por más de tres décadas. Actualmente, se ha reconocido la participación del estrés oxidativo y la activación de procesos inflamatorios que hacen susceptibles al hospedero de desarrollar patologías subyacentes que requieren entenderse en el contexto de la enfermedad. Entre las manifestaciones causadas por el desbalance en el metabolismo de lípidos, se encuentra la lipodistrofia, dislipidemia, resistencia a la insulina e hipertensión, factores que incrementan el riesgo cardiovascular. Las investigaciones recientes sugieren que las lipoproteínas de alta densidad (HDL) desempeñan un papel crucial en el incremento del riesgo cardiovascular, no solamente por los cambios en su concentración circulante, sino también por cambios en su función, lo cual ha sido objeto de estudio para crear nuevos tratamientos. Por tanto se realizó una revisión, mediante la búsqueda de información primaria y secundaria en tres bases electrónicas de artículos científicos publicados en el año 1986 a 2023, con el fin de analizar el papel de las HDL en la regulación de procesos oxidativos e inflamatorios en pacientes VIH+, los mecanismos que favorecen su disfuncionalidad, así como las estrategias terapéuticas para disminuir el riesgo cardiovascular al incrementar la funcionalidad de las HDL.
Background & aims:
Growing evidence suggests an important role of B cells in the development of non-alcoholic fatty liver disease (NAFLD). However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking.
Approach & results:
In wildtype mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, while HFD feeding in wildtype mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wildtype and IgMi mice. HFD reduced the number of regulatory B cells and interleukin 10 production in the liver of wildtype mice, while these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG, stromal B cells and low numbers of interleukin 10 expressing cells, compatible with our experimental data.
Conclusions:
B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. Interleukin 10-producing regulatory B cells may represent such a protective B cell subset.
La maladie du greffon contre l’hôte aigüe (GVHa) est une complication majeure de l’allogreffe de cellules hématopoïétiques (alloCH) associée à une mortalité et une morbidité importantes. Les lipopolysaccharides (LPS) sont des signaux de danger impliqués dans l’activation des cellules présentatrices de l’antigène (CPA), la sécrétion de cytokines pro-inflammatoires et l’entretien des lésions épithéliales intestinales. Dans ce contexte, rompre la cascade inflammatoire initiée par les LPS semble être une approche originale pour prévenir le développement de la GVHa. Ainsi, notre groupe se propose d’évaluer l’impact du Reverse LPS Transport (RLT) dans la physiopathologie de la GVH. Le RLT est une voie analogue au transport inverse du cholestérol qui correspond au transfert de molécules lipophiles vers les lipoprotéines de haute densité (HDL) pour leur élimination biliaire.En utilisant des modèles expérimentaux de GVHa, nous avons confirmé l’exposition aux LPS des souris receveuses par une technique basée sur la spectrométrie de masse. Nous avons ensuite exploré l’impact du RLT en modulant plusieurs effecteurs ou régulateurs potentiels. Nos principaux résultats montrent que :i)En absence totale de HDL (c.-à-d. des souris ApoA1tm1Unc knock-out), la mortalité et la sévérité de la GVHa sont augmentées chez les souris receveuses. Cette aggravation est associée à une accélération de la maturation des APC et une élévation des réponses lymphocytaires de type 1 dans la rate et le foie.ii)La concentration de HDL est effondrée dans le plasma des souris allogreffées, mais elle peut être corrigée par l’administration répétée de HDL isolées à partir de plasma humain. La restauration du taux de HDL circulantes permet d’améliorer significativement la survie et le score clinique des souris transplantées. De plus, l’administration de HDL réduit la concentration de LPS plasmatique et biliaire, la capacité des splénocytes à activer des lymphocytes T allogéniques et la production de cytokines pro-inflammatoires par les APC hépatiques.L’ensemble de ces données suggère que l’administration de HDL pourrait être une stratégie prophylactique pour prévenir la GVHa.
Background
Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.
Objective
To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.
Methods
Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.
Results
Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein–kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.
Conclusion
Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.
Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL (high-density lipoprotein) and apolipoprotein A-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics, and 163 non-asthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and nuclear magnetic resonance (NMR) spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys Periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL-cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR. In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.
Different pharmacological interventions have been applied with success to reduce the progression of atherosclerosis. However, many patients are not good responders or must interrupt treatment due to adverse effects. Bioactive compounds such as omega-3 fatty acids (n-3 FA), plant sterol esters (PSE) and phenolic compounds (PHC) are natural molecules with great potential to reduce the atherosclerosis burden by reducing inflammation, LDL cholesterol (LDL-C) and oxidative stress, respectively. Although their physiological effects on biomarkers are much lower than those expected by drugs used for the same purpose, bioactive compounds can easily be incorporated into the daily diet and present no adverse effects. However, little is known about the combination of n-3 FA, PSE, PHC and drugs in atherosclerosis progression. This review article summarizes potential effects of co-therapies involving n-3 FA, PSE and PHC combined with major hypolipidemic drugs on atherosclerosis biomarkers and clinical outcomes. Evidence of additive and/or complementary effects regarding drugs action reveals possible roles for bioactive compounds in disease management. Pharmaceutical companies, physicians and food scientists should be prepared to better understand this type of interaction and its consequences in terms of efficacy and life quality.
Background
Atherosclerosis is a chronic inflammatory disorder whose development is inversely correlated with high‐density lipoprotein concentration. Current therapies involve pharmaceuticals that significantly elevate plasma high‐density lipoprotein cholesterol concentrations. Our studies were conducted to investigate the effects of low‐dose lipid‐free apolipoprotein A‐I (apoA‐I) on chronic inflammation. The aims of these studies were to determine how subcutaneously injected lipid‐free apoA‐I reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without sustained elevations in plasma high‐density lipoprotein cholesterol concentrations.
Methods and Results
Ldlr −/− and Ldlr −/− apoA‐I −/− mice were fed a Western diet for a total of 12 weeks. After 6 weeks, a subset of mice from each group received subcutaneous injections of 200 μg of lipid‐free human apoA‐I 3 times a week, while the other subset received 200 μg of albumin, as a control. Mice treated with lipid‐free apoA‐I showed a decrease in cholesterol deposition and immune cell retention in the aortic root compared with albumin‐treated mice, regardless of genotype. This reduction in atherosclerosis appeared to be directly related to a decrease in the number of CD 131 expressing cells and the esterified cholesterol to total cholesterol content in several immune cell compartments. In addition, apoA‐I treatment altered microdomain cholesterol composition that shifted CD 131, the common β subunit of the interleukin 3 receptor, from lipid raft to nonraft fractions of the plasma membrane.
Conclusions
ApoA‐I treatment reduced lipid and immune cell accumulation within the aortic root by systemically reducing microdomain cholesterol content in immune cells. These data suggest that lipid‐free apoA‐I mediates beneficial effects through attenuation of immune cell lipid raft cholesterol content, which affects numerous types of signal transduction pathways that rely on microdomain integrity for assembly and activation.
Purpose of review:
This article describes recent findings regarding lipid metabolism in critical illness as well as in lipid therapy.
Recent findings:
In critical illness, in the presence of a decrease in lipid absorption, adipose tissue lipolysis raises triglyceride levels. High-density lipoprotein and low-density lipoprotein are decreased because of impairment of lecithin-cholesterol acyltransferase, mainly in sepsis. In septic patients, lipid profile may be a predictor of survival. Nonsurvivors have lower levels of high-density lipoprotein and low-density lipoprotein. In metabolomic studies, most of the changes from baseline in septic patients were related to lipid metabolism. Lysophosphatidylcholine was also significantly lower in nonsurviving septic patients.
Summary:
Lipid profile results are too often neglected by the clinician despite increasing knowledge in the modifications related to septic state as well as the importance of these values in the prognosis of the critically ill. Lipid administration (enterally or parenterally) should be guided by better knowledge of the lipid metabolism of the patient.
Introduction:
Although there has been great progress achieved by the use of intensive statin therapy, the burden of atherosclerotic cardiovascular disease (CVD) remains high. This has initiated the search for novel high-density lipoprotein (HDL)-based therapeutics. Recent years have witnessed a shift from traditional raising HDL-C levels to enhancing HDL functionality, in which the process of reverse cholesterol transport (RCT) has acquired much attention.
Areas covered:
In this review, the authors describe the key factors involved in RCT process for potential drug targets to reduce the CVD risk. Furthermore, the review provides a summary of the effective screening methods that have been developed to target RCT and their applications. This review also introduces some new strategies currently being clinically developed, which have the potential to improve HDL function in the RCT process.
Expert opinion:
It is rational that the functionality of HDL is more important than the plasma HDL-C level in the evaluation of pharmacological treatment in atherosclerosis. HDL-based strategies designed to promote macrophage RCT are a major area of current drug discovery and development for atherosclerotic diseases. A better understanding of the functionality of HDL and its relationship with atherosclerosis will expand our knowledge of the role of HDL in lipid metabolism, holding promise for a future successful HDL-based therapy.
Research in cardiovascular biology and disease is influenced by the changing landscape in biomedical and health research. Increased demands for innovation, translation, and implementation of novel findings into patient care are reflected in growth of publications and journals with more clinical and translational content, and more emphasis on the potential impact of basic and preclinical research in basic science reports. At the same time there has been an exciting growth of pure exploratory basic research, related to technological innovation, e.g. advanced microscopy, rewarded with the 2014 Nobel …
High-density lipoproteins (HDLs) have captured the imagination of scientists and physicians from virtually the time they were originally described, but especially after the cholesterol carried in HDL (HDL-C) was shown to be strongly and inversely associated with risk of coronary heart disease (CHD).1 This observation, replicated in many populations around the world, has led to the popular view of HDL-C as the ‘good cholesterol’ and to the belief that intervention to raise plasma levels of HDL-C would lead to reduction in risk of CHD (the ‘HDL hypothesis’). Because of its obvious clinical relevance, the structure, function, metabolism, and regulation of HDL has been studied in great detail by hundreds of laboratories around the world. The science and biology of HDL is a mature field that has been informed by structural biology, lipid and protein biochemistry, model systems, human genetics and physiology, and pharmacology. Although much has been learned, there remain major questions surrounding HDL, not the least of which includes recent scepticism about the fundamental HDL hypothesis.
Two major developments over the last few years, in human genetics and clinical trials with pharmacological agents, have led to doubts about the HDL hypothesis. Human genetics have taught us a great deal about HDL metabolism. Mendelian disorders of extreme low and high HDL-C levels have been extremely informative regarding the key roles of specific proteins.2 More recently, unbiased genome-wide studies have led to scores of additional loci associated with HDL-C levels.3 A focus of intense interest has been the relationship between genetic factors that influence HDL-C levels and risk of CHD. It is interesting that despite decades of study, the three Mendelian causes of extremely low HDL-C — apoA-I structural mutations, …
BACKGROUND
Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib.
METHODS
We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina.
RESULTS
At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.
CONCLUSIONS
Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264. opens in new tab.)
Aims:
Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events.
Methods and results:
Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ~1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6-7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3× upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants.
Conclusion:
The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years.
Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new Cholesteryl Ester Transfer Protein (CETP) inhibitor, in healthy subjects.
Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, >65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.
Peak TA-8995 concentrations occurred approximately 4 hours post-dose. Mean half-lives ranged from 81 to 166 hours, without an obvious dose-relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased HDL-C by 96 to 140% and decreased LDL-C by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in Apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.
TA-8995 is a potent CETP inhibitor and warrants further investigation.
Significance
Bromo and extraterminal (BET) proteins have diverse roles in regulating tissue-specific transcriptional programs, raising safety concerns for their inhibition and suggesting that targeting of specific isoforms or even specific domains within this subfamily is important. We report the discovery and characterization of RVX-208 as a domain-selective inhibitor of BETs and provide a potential mechanism of action of a clinical compound that was identified based on phenotypic screens.
We recently reported that levels of unsaturated lysophosphatidic acid (LPA) in the small intestine significantly correlated with the extent of aortic atherosclerosis in LDLR(-/-) mice fed a Western Diet (WD). Here we demonstrate that WD increases unsaturated (but not saturated) LPA levels in small intestine of LDLR(-/-) mice and causes changes in small intestine gene expression. Confirmation of microarray analysis by RT-qPCR showed that adding transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F) to WD prevented many WD-mediated small intestine changes in gene expression. If instead of feeding WD, unsaturated LPA was added to chow and fed to the mice, i) levels of LPA in small intestine were similar to those induced by feeding WD; ii) gene expression changes in small intestine mimicked WD-mediated changes; and iii) changes in plasma serum amyloid A (SAA), total cholesterol, triglycerides, HDL-cholesterol levels, and FPLC lipoprotein profile mimicked WD-mediated changes. Adding Tg6F (but not control tomatoes) to LPA-supplemented chow prevented the LPA-induced changes. We conclude that i) WD-mediated systemic inflammation and dyslipidemia may be in part due to WD-induced increases in small intestine LPA levels; ii) Tg6F reduces WD-mediated systemic inflammation and dyslipidemia by preventing WD-induced increases in LPA levels in small intestine.
The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Our objective was to produce and characterize a human apolipoprotein AI (apoAI) product optimized to treat clinical atherosclerotic disease.
A new formulation of full length, plasma-derived human apoAI termed CSL112 was designed to maximize the cholesterol efflux from cells and exhibit favorable pharmacological properties. CSL112 is a disc-shaped particle that strongly elevates cholesterol esterification and shows good pharmacokinetics in rabbits. Infusion of CSL112 into rabbits caused a strong and immediate increase in the ABCA1-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In the presence of human plasma, CSL112 was significantly more potent than native HDL at enhancing cholesterol efflux from macrophages, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of very small HDL, a favorable substrate for ABCA1. The lipid profile of plasma did not affect these behaviors. In studies with whole human blood, CSL112 reduced expression of ICAM1 and cytokine secretion, and as with cholesterol efflux, these activities were substantially greater than those of native HDL assayed in parallel.
CSL112 has favorable pharmacological properties and strongly elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal and this property makes CSL112 a promising candidate therapy for acute coronary syndrome.
The regulation of synthesis, degradation, and distribution of lipids is crucial for homeostasis of organisms and cells. The sterol regulatory element-binding protein (SREBP) transcription factor family is post-translationally activated in situations of reduced lipid abundance and activates numerous genes involved in cholesterol, fatty acid, and phospholipid synthesis. In this study, we provide evidence that the primary transcript of SREBP2 contains an intronic miRNA (miR-33) that reduces cellular cholesterol export via inhibition of translation of the cholesterol export pump ABCA1. Notably, miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation. The genetic locus encoding SREBP2 and miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids. These results add an additional layer of complexity to our understanding of lipid homeostasis and might open possibilities for future therapeutic intervention.
Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach.
ABCAI, a member of the ATP binding cassette family, mediates the efflux of excess cellular lipid to HDL and is defective in Tangier disease. The apolipoprotein acceptor specificity for lipid efflux by ABCAI was examined in stably transfected Hela cells, expressing a human ABCAI–GFP fusion protein. ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI–GFP transfected cells compared to control cells. Expression of ABCAI in Hela cells also resulted in a marked increase in specific binding of both apoA-I (Kd = 0.60 μg/mL) and apoA-II (Kd = 0.58 μg/mL) to a common binding site. In summary, ABCAI-mediated cellular binding of apolipoproteins and lipid efflux is not specific for only apoA-I but can also occur with other apolipoproteins that contain multiple amphipathic helical domains.
Aims:
High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).
Methods and results:
Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).
Conclusion:
The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.
In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk.
We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.
A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test).
Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289.).
Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr-/- mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.
A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk.
In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux.
We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.
In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It is unclear what role SR-BI plays in human metabolism.
We sequenced the gene encoding SR-BI in persons with elevated HDL cholesterol levels and identified a family with a new missense mutation (P297S). The functional effects of the P297S mutation on HDL binding, cellular cholesterol uptake and efflux, atherosclerosis, platelet function, and adrenal function were studied.
Cholesterol uptake from HDL by primary murine hepatocytes that expressed mutant SR-BI was reduced to half of that of hepatocytes expressing wild-type SR-BI. Carriers of the P297S mutation had increased HDL cholesterol levels (70.4 mg per deciliter [1.8 mmol per liter], vs. 53.4 mg per deciliter [1.4 mmol per liter] in noncarriers; P<0.001) and a reduced capacity for efflux of cholesterol from macrophages, but the carotid artery intima-media thickness was similar in carriers and in family noncarriers. Platelets from carriers had increased unesterified cholesterol content and impaired function. In carriers, adrenal steroidogenesis was attenuated, as evidenced by decreased urinary excretion of sterol metabolites, a decreased response to corticotropin stimulation, and symptoms of diminished adrenal function.
We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).
Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.
The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3' UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.
Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy.
Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA)
located within the gene encoding sterol-regulatory element–binding factor–2 (SREBF-2), a transcriptional regulator of cholesterol
synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33
inhibits the expression of the adenosine triphosphate–binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol
efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density
lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL
levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33
appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.
Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element–binding
proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here
that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate–binding cassette transporter
A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional
repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased
cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid–antisense oligonucleotides results
in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol
homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.
Here, we report the creation of a single-helix peptide (ATI-5261) that stimulates cellular cholesterol efflux with K(m) molar efficiency approximating native apolipoproteins. Anti-atherosclerosis activity of ATI-5261 was evaluated in LDLR(-/-) and apolipoprotein (apo)E(-/-) mice approximately 5-7 months of age, following 13-18 weeks on a high-fat Western diet (HFWD). Treatment of fat-fed LDLR(-/-) mice with daily intraperitoneal injections of ATI-5261 (30 mg/kg) for 6 weeks reduced atherosclerosis by 30%, as judged by lesion area covering the aorta (7.9 +/- 2 vs.11.3 +/- 2.5% control, P = 0.011) and lipid-content of aortic sinus plaque (25 +/- 5.8 vs. 33 +/- 4.9% control, P = 0.014). In apoE(-/-) mice, the peptide administered 30 mg/kg ip on alternate days for 6 weeks reduced atherosclerosis by approximately 45% (lesion area = 15 +/- 7 vs. 25 +/- 8% control, P = 0.00016; plaque lipid-content = 20 +/- 6 vs. 32 +/- 8% control, P < 0.0001). Similar reductions in atherosclerosis were achieved using ATI-5261:POPC complexes. Single intraperitoneal injection of ATI-5261 increased reverse cholesterol transport from macrophage foam-cells to feces over 24-48 h. In summary, relatively short-term treatment of mice with the potent cholesterol efflux peptide ATI-5261 reduced substantial atherosclerosis. This was achieved using an L-amino acid peptide, in the presence of severe hypercholesterolemia/HFWD, and did not require daily injections or formulation with phospholipids when administered via intraperitoneal injection.
Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both compari...
Introduction: Lecithin cholesterol acyltransferase (LCAT) is a liver-derived enzyme in plasma that catalyzes the formation of cholesteryl esters (CE). Mutations in the human LCAT gene result in familial LCAT deficiency (FLD), characterized by absent high-density lipoprotein cholesterol (HDL-C), corneal opacities, anemia, and severe renal disease. Replacing the defective enzyme should restore the normal level of plasma CE (LCAT product) and lead to the appearance of alpha HDL (α-HDL) lipoproteins.
Aim: To assess the formation of CE and the appearance of HDL over time in a FLD patient with recombinant human LCAT (ACP-501).
Methods: A FLD subject with very low HDL-C (<5 mg/dL), corneal opacities, stage 4/5 renal disease, anemia, and splenomegaly received a 1 hour infusion of recombinant human LCAT (rhLCAT) and serial plasma samples were collected over 7 days.
Results: HDL-C increased from <5 mg/dL to 17 mg/dL at 8 hours and remained measurable for 7 days. CE increased rapidly, doubling in concentration within 2 hours, and sustained a higher concentration than HDL over 7 days. An increase in LDL-C was delayed about 6 hours suggesting CETP transfer of CE from HDL to LDL. Small sized particles were rapidly converted to HDL2 and HDL3 sized particles on FPLC. Large α-HDL appeared on agarose electrophoresis within 30 minutes. ApoAI Western blot analysis confirmed the rapid generation of apoAI staining α-HDL. α-1, 2 and 3 particles rapidly appeared by 2-D gel electrophoresis. Filipin stained 1-D gels revealed large α particles that persisted for 7 days. α-4 sized particles decreased as α-HDL formed. Sudan stained 1-D gels showed the generation of CE-rich α-HDL.
Conclusions: The infusion of rhLCAT (ACP-501) in a lecithin cholesterol acyltransferase deficient subject with no HDL rapidly generated CE and α-HDL with evidence of sustained activity over 7 days. CE appeared in LDL suggesting the transfer of CE from HDL to LDL by CETP. The lipid and lipoprotein changes are consistent with normal HDL maturation.
For every 1% increase in circulating HDL cholesterol (HDL-C), there is a 2% decrease in overall risk for development of coronary artery disease (Wilson PW. Am J Cardiol 1990;66:7A-10A). It has been found in mouse models of atherosclerosis that over expression of apoA1, which increases HDL levels, hinders plaque progression and promotes plaque regression (Plump AS, et al. Proc Natl Acad Sci USA 1994;91:9607-11 and Rong JX, et al. Circulation 2001;104:2447-52). Such evidence has stimulated an interest in therapies to raise HDL levels. Despite the fact HDL raising strategies may be effective therapy for atherosclerosis, the underlying mechanisms that contribute to HDL regulation and its manipulation for therapy remain poorly understood.
New therapeutic strategies are needed for the rapid stabilization of acute coronary syndrome (ACS) patients by treating nonculprit lesions. Reconstituted HDL (rHDL), which is apoA-I combined with phospholipids, is currently being tested in clinical trials for this purpose and is the subject of this review.
At least four different formulations (SRC-rHDL, CSL-111, CSL-112 and ETC-216) have been tested in clinical trials. The various rHDL preparations have been shown to be effective in the rapid mobilization of excess cholesterol from cells and in regressing atherosclerotic plaques in animal models. Two of the rHDL agents, namely ETC-216 and CSL-111, have been shown to be effective after only a few treatments in reducing plaque volume in ACS patients, as assessed by intravascular ultrasound, but no clinical trials assessing clinical endpoints have yet been completed.
rHDL is a promising new potential therapy for ACS patients, but much work remains to be done, and there are many unresolved questions. Progress in developing rHDL into a therapy will depend on improving our understanding of their mechanism of action, determining the optimum formulation and delivery and how to monitor rHDL therapy.
Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. Mutations in the LCAT gene leads to two rare disorders, familial LCAT deficiency and fish-eye disease, both characterized by severe hypoalphalipoproteinemia associated with several lipoprotein abnormalities. No specific treatment is presently available for genetic LCAT deficiency. In the present study, recombinant human LCAT was expressed and tested for its ability to correct the lipoprotein profile in LCAT deficient plasma. The results show that rhLCAT efficiently reduces the amount of unesterified cholesterol (-30%) and promotes the production of plasma cholesteryl esters (+210%) in LCAT deficient plasma. rhLCAT induces a marked increase in HDL-C levels (+89%) and induces the maturation of small preβ-HDL into alpha-migrating particles. Moreover, the abnormal phospholipid-rich particles migrating in the LDL region were converted in normally sized LDL.
The apolipoprotein A-I-Milano (apoA-I-M) is a molecular variant of apoA-I characterized by the Arg(173)-->Cys substitution, resulting in the formation of homodimers A-I-M/A-I-M. The introduction of the interchain disulfide bridge in the A-I-M dimer limits the apolipoportein conformational flexibility and restricts HDL particle size heterogeneity, thus possibly affecting HDL function in lipid metabolism and atherosclerosis protection. To investigate whether the structural changes in A-I-M/A-I-M? affect apoA-I capacity for cell cholesterol uptake, we tested the ability of four reconstituted HDL (rHDL), that contained either apoA-I or A-I-M/A-I-M, to remove cholesterol from Fu5AH hepatoma cells and cholesterol-loaded murine primary macrophages (MPM). As the HDL particle size is known to affect the rHDL capacity for cell cholesterol uptake, the reconstitution conditions were carefully selected to produce two sets of rHDL particles of small and large size (7.8 and 12.5 nm in diameter). The small A-I-M/A-I-M rHDL were more efficient than the corresponding apoA-I particles as accepters of membrane cholesterol from Fu5AH cells and MPM, and as inhibitors of cholesterol esterification in MPM. The large rHDL and the lipid-free apolipoproteins displayed instead similar capacities for cell cholesterol efflux, These results suggest that cell cholesterol efflux to rHDL particles of different size occurs through different mechanisms. Large HDL accommodate and retain the cholesterol molecules that have desorbed from the cell membrane into the extracellular fluid, in a process that is less sensitive to protein conformation. Small HDL accelerate the desorption of cholesterol from the cell membrane, in a process that is influenced by the conformation of the proteins on the surface of the acceptor particle. The enhanced efficiency of small A-I-M/A-I-M rHDL seems related to the peculiar structure of the protein on the rHDL surface, with a hydrophobic C-terminal domain extending out of the rHDL particle, available for anchoring the acceptor to the plasma membrane.
Objectives:
Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease.
Design:
A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min⁻¹] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects.
Results:
Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917-0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group.
Conclusions:
CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.
Although the inverse relationship between plasma levels of high-density lipoprotein (HDL) and cardiovascular disease has been largely demonstrated, many observations have suggested that the assessment of HDL functionality might be more informative than a simple measurement of HDL-cholesterol plasma levels. HDLs are a class of structurally and functionally heterogeneous particles; in atherosclerosis-related diseases, changes in HDL subfraction levels and functions are frequently observed. Circulating levels of large HDL particles are decreased in dyslipidaemic conditions, while levels of small dense HDL particles are increased in patients with coronary heart disease. Furthermore, specific genetic defects in proteins involved in HDL metabolism significantly impact the distribution of HDL subpopulations. Finally, many drugs used for dyslipidaemia induce changes in HDL subfractions strictly related to cardiovascular disease. Although several methods exist to evaluate HDL subclass levels, most of them are not easily applicable in clinical practice, due to the costs and high variability. However, the possibility to measure the levels of specific HDL subfractions in patients with atherosclerosis-related diseases might help to better define their cardiovascular risk.
Low density lipoproteins (LDL) and high density lipoproteins (HDL) are independent risk factors for coronary heart disease (CHD); decreasing LDL-cholesterol (LDL-C) levels with statin therapy represents the primary goal in the management of cardiovascular disease. However, despite the efficacy of statins in reducing cardiovascular morbidity and mortality, a significant residual risk has been observed even after reaching the LDL-C target, suggesting that other risk factors beyond LDL-C should be addressed, including low levels of HDL-cholesterol (HDL-C). Several clinical trials have shown an inverse relationship between HDL-C levels and cardiovascular risk, and 1 mg/dl increment in HDL-C is associated in epidemiological studies with a 2-3% decrease in cardiovascular risk, suggesting that raising HDL-C levels might have beneficial effects to reduce cardiovascular disease. However, several lines of evidence indicate that the functional properties of HDL may be relevant as well. In patient with CAD and normal HDL-C levels, HDL exhibit significantly reduced protective functions, and rather appear to be pro-atherogenic; on the other hand some genetic mutations causing low levels of HDL-C are not associated with increased atherosclerosis. Furthermore, although niacin significantly increased HDL-C levels, no further clinical benefit was observed from the addition of niacin to statin therapy, suggesting that increasing HDL-C levels is not sufficient and perhaps functional properties of HDL must be considered when choosing a therapeutic strategy to reduce the residual cardiovascular risk.
MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression at the post-transcriptional level that have been involved in the pathogenesis of a number of cardiovascular diseases. Several miRNAs have been described to finely regulate lipid metabolism and the progression and regression of atherosclerosis including, miR-33, miR-122. Of note miR-33a and -33b, represent one of the most interesting and attractive targets for metabolic-related disorders and anti-miR-33 approaches are under intensive investigation. More recently miRNAs were shown to exert their activities in a paracrine manner and also systemically. The latter is possible because lipid-carriers, including lipoproteins, transport and protect miRNAs from degradation in the circulation. This review will present the complex mechanism by which miRNAs regulate lipid metabolism, illustrate how their therapeutical modulation may lead to new treatments for cardiometabolic diseases, and discuss how lipoproteins and other lipid-carriers transport miRNAs in the circulation. The emerging strong connection between miRNAs, lipoproteins and lipid metabolism indicates the existence of a reciprocal modulation that might go beyond atherosclerosis.
More than 1 million people in the United States experience an acute coronary syndrome (ACS) every year, and almost 600,000 undergo percutaneous coronary intervention (PCI) for treatment of cardiovascular disease. There is a large amount of evidence-based literature to guide appropriate management of these patients. There have been a number of advances in the treatment of these patients over the last several years. Due to the large amount of rapidly available literature concerning the care of patients with ACS or undergoing PCI, clinicians can often find it difficult to keep up with the information needed for optimizing care of these patients. Therefore, we provide the second update to the first compiled bibliography of key articles and guidelines relative to patients with ACS published in Pharmacotherapy in 2004. The initial update was published in Pharmacotherapy in 2007 and also included bibliographies concerning management of patients undergoing PCI. A number of guidelines and practice-changing literature have been published since the update in 2007. Specific areas included in this review are updated summaries of clinical practice guidelines and clinical trials of anticoagulants, antiplatelets, platelet aggregation testing, pharmacogenomics testing in patients taking clopidogrel, clopidogrel loading dose comparisons, clopidogrel and proton pump inhibitor drug interactions, the impact of bleeding in ACS, and statins. As with previous versions of this document, we hope that this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with coronary heart disease.
The regulation of synthesis, degradation, and distribution of lipids is crucial for homeostasis of organisms and cells. The
sterol regulatory element-binding protein (SREBP) transcription factor family is post-translationally activated in situations
of reduced lipid abundance and activates numerous genes involved in cholesterol, fatty acid, and phospholipid synthesis. In
this study, we provide evidence that the primary transcript of SREBP2 contains an intronic miRNA (miR-33) that reduces cellular cholesterol export via inhibition of translation of the cholesterol
export pump ABCA1. Notably, miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid
β-oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation. The genetic locus encoding SREBP2 and
miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly
synthesized lipids. These results add an additional layer of complexity to our understanding of lipid homeostasis and might
open possibilities for future therapeutic intervention.
This review highlights the diverse roles of the high-affinity HDL receptor scavenger receptor class B, type I (SR-BI) in the modulation of global cholesterol homeostasis and vascular cell function, and the potential implications of these processes in atherosclerosis.
SR-BI in the liver plays a critical role in reverse cholesterol transport and it dramatically impacts the characteristics of the HDL particle, and through reverse cholesterol transport it promotes an antiatherogenic lipid environment in the vascular wall. SR-BI in macrophages may influence their inflammatory phenotype. In endothelial cells, SR-BI mediates HDL-induced endothelial nitric oxide synthase activation and proliferation and migration, and in platelets SR-BI may be prothrombotic in the setting of dyslipidemia. Several polymorphisms of SR-BI have been reported in humans that influence receptor expression or function.
In addition to regulating global lipid metabolism, SR-BI influences the functions of a variety of vascular cells relevant to atherosclerosis. Studies of SR-BI genetics in humans partially support the conclusions drawn from experimental models. However, because of the multiple functions of SR-BI, the diversity of cell types in which it is expressed, and the influence of the receptor on the characteristics of its own ligand, our understanding of the biology of the receptor is just emerging.
High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities.1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux,2,3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport” (RCT) process; however, macrophage-derived cholesterol represents a minor component of the cholesterol transported by HDL particles.4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) A-I complexes (pre-β migrating HDL or very small HDL [HDL-VS]; Figure 2).1,8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterol-containing α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDL-VL).1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol …
Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.
The lecithin:cholesterol acyltransferase (LCAT) enzyme is responsible for the synthesis of cholesteryl esters in human plasma and plays a critical role in high density lipoprotein (HDL) metabolism. Genetic LCAT deficiency is a rare metabolic disorder characterized by low HDL cholesterol levels. This paper reviews the genetic and biochemical features of LCAT deficiency, highlighting the absence of enhanced preclinical atherosclerosis in carriers, despite the remarkably low HDL cholesterol.
Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C). The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C.
Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.
In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.
189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.
Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.
F Hoffmann-La Roche Ltd.
HDLs possess several physiological activities that may explain their antiatherosclerotic properties. Among them, the most relevant is the ability of HDL to promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion.
The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis, including monocyte-macrophages, B and T lymphocytes. HDL also acts as a reservoir for a number of biologically active substances that may impact the immune system, and as the HDL composition varies to a large extent during inflammation.
The understanding of how these interactions take place and how biologically active substances can be delivered to relevant targets during atherogenesis is of great interest and may provide a better understanding for the role of HDL in atherogenesis.
High density lipoproteins (HDL) possess a number of physiological activities. The most studied and, perhaps, better understood is the ability of HDL to promote excess cholesterol efflux from peripheral tissues and transport to the liver for excretion, a mechanism believed to confer protection against atherosclerotic cardiovascular disease. The ability of HDL to modulate cholesterol bioavailability in the lipid rafts, membrane microdomains enriched in glycosphingolipids and cholesterol, is evolutionary conserved and affects the properties of cells involved in the innate and adaptive immune response, tuning inflammatory response and antigen presentation functions in macrophages as well as B and T cell activation. Also sphingosine-1 phosphate (S1P), a major active sphingolipid carried by HDL, is of relevance in the pathogenesis of several immuno-inflammatory disorders through the modulation of macrophage and lymphocyte functions. Furthermore, HDL influence the humoral innate immunity by modulating the activation of the complement system and the expression of pentraxin 3 (PTX3). Finally, in humans, HDL levels and functions are altered in several immune-mediated disorders, such as rheumatoid arthritis, systemic lupus eritematosus, Crohn's disease and multiple sclerosis as well as during inflammatory responses. Altogether these observations suggest that the effects of HDL in immunity could be related, to either the ability of HDL to modulate cholesterol content in immune cell lipid rafts and to their role as reservoir for several biologically active substances that may impact the immune system.
Brunham LR, Tietjen I, Bochem AE, Singaraja RR, Franchini PL, Radomski C, Mattice M, Legendre A, Hovingh GK, Kastelein JJP, Hayden MR. Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans.
The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C). Here we report two additional individuals with extremely high HDL-C (greater than the 90th percentile for age and gender) with rare mutations in the gene encoding SR-BI. These mutations segregate with high HDL-C in family members of each proband and are associated with a 37% increase in plasma HDL-C in heterozygous individuals carrying them. Both mutations occur at highly conserved positions in the large extracellular loop region of SR-BI and are predicted to impair the function of the SR-BI protein. Our findings, combined with the prior report of a single mutation in the gene encoding SR-BI, further validate that mutations in SR-BI are a rare but recurring cause of elevated HDL-C in humans.
The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis.
No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development.
A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated.
For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels.
Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018).
Apolipoprotein mimetic peptides are short synthetic peptides that share structural, as well as biological features of native apolipoproteins. The early positive clinical trials of intravenous preparations of apoA-I, the main protein component of high density lipoproteins (HDL), have stimulated great interest in the use of apolipoprotein mimetic peptides as possible therapeutic agents. Currently, there are a wide variety of apolipoprotein mimetic peptides at various stages of drug development. These peptides typically have been designed to either promote cholesterol efflux or act as anti-oxidants, but they usually exert other biological effects, such as anti-inflammatory and anti-thrombotic effects. Uncertainty about which of these biological properties is the most important for explaining their anti-atherogenic effect is a major unresolved question in the field. Structure-function studies relating the in vitro properties of these peptides to their ability to reduce atherosclerosis in animal models may uncover the best rationale for the design of these peptides and may lead to a better understanding of the mechanisms behind the atheroprotective effect of HDL.
Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.
Technological advances have enhanced our ability to visualize the entire extent of atherosclerosis within the artery wall. Intravascular ultrasound has enabled characterization of the impact of medical therapies on progression of coronary atherosclerosis. Despite use of established anti-atherosclerotic therapy, cardiovascular disease still remains the leading cause of morbidity and mortality. There is an ongoing need to develop new therapeutic strategies to achieve more effective reduction in cardiovascular risk. Raising high-density lipoprotein cholesterol continues to receive attention as a therapeutic strategy. The relationship between high-density lipoprotein and progression of atherosclerosis and its implications for clinical practice are reviewed here.
microRNAs (miRs) are short, approximately 22-nucleotide-long non-coding RNAs involved in the control of gene expression. They guide ribonucleoprotein complexes that effect translational repression or messenger RNA degradation to targeted messenger RNAs. miRs were initially thought to be peculiar to the developmental regulation of the nematode worm, in which they were first described in 1993. Since then, hundreds of different miRs have been reported in diverse organisms, and many have been implicated in the regulation of physiological processes of adult animals. Of importance, misexpression of miRs has been uncovered as a pathogenic mechanism in several diseases. Here, we first outline the biogenesis and mechanism of action of miRs, and then discuss their relevance to heart biology, pathology, and medicine.
Metabolic syndrome, diabetes and obesity are frequently associated with hypertriglyceridemia, hypercholesterolemia and low HDL levels, a phenotype known as atherogenic dyslipidemia. Atherogenic dyslipidemia and hypertriglyceridemia are frequently treated with fibric acid derivatives which activate the nuclear receptor PPAR-alpha leading to reduce plasma triglycerides and an increase in HDL cholesterol levels. The mechanism by which activation of PPAR-alpha with fibrates improves the plasma lipid profile in patients with atherogenic dyslipidemia and hypertriglyceridemia has been examined in several small studies measuring lipoprotein kinetics. The results of these studies indicate that the changes in lipoprotein metabolism observed in response to fibrate treatment vary according to lipoprotein phenotype. In general, fibrates act to reduce VLDL apoB-100 through enhanced fractional catabolism (clearance) of VLDL apoB-100 with additional effects on reducing VLDL apoB-100 production. LDL apoB-100 levels generally decrease in response to fibrates due to increased LDL fractional catabolism except in those patients with high to very high plasma triglyceride levels (>400mg/dL). Fibrates also increase HDL apoA-I and apoA-II levels by enhancing apoA-I and apoA-II production, although this is partially counteracted by increasing fractional catabolism of these apolipoproteins. The potent and specific PPAR-alpha agonist LY518674, reduced VLDL apoB-100 levels through enhanced fractional catabolism similar to what is seen with fibrates. In contrast to fibrates, LY518674 did not change HDL apoA-I levels in response to due to an increased turnover of apoA-I where an increased fractional catabolic rate entirely counteracted the increase in apoA-I production. The changes in apoB metabolism in response to PPAR-alpha activation with fibrates and specific PPAR-alpha agonists would be expected to reduce the risk of cardiovascular disease. However, the benefit of the enhanced turnover of HDL apoA-I in response to PPAR-alpha activation remains to be determined.