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Biology and pathology of chylomicron triglyceride catabolism. Graphic symbology: open, double-surrounded ellipsoids indicate gene targets. Red circles indicate gene targets with known causal loss-of-function mutations in familial hyperchylomicronemia: LPL (1), apoC-II (2), GPIHBP1 (3), LMF1 (4), apoA-V (5). FA, fatty acids; GPIHBP1, glycophosphatidylinositol HDL-binding protein-1; HSPG, heparan sulfate proteoglycans; LMF-1, lipase maturation factor-1; LPL, lipoprotein lipase; TG, triglycerides. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Source publication
The adequate absorption of lipids is essential for all mammalian species due to their inability to synthesize some essential fatty acids and fat-soluble vitamins. Chylomicrons (CMs) are large, triglyceride-rich lipoproteins that are produced in intestinal enterocytes in response to fat ingestion, which function to transport the ingested lipids to d...
Contexts in source publication
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... in the apoA-V-mediated modu- lation of lipoprotein lipase action [34]. First, it has been suggested that the interaction between apoA-V and glycosylphosphatidylinositol- anchored high-density lipoprotein binding protein 1 (GPIHBP1) might favor the triglyceride hydrolysis of TRLs in mediating the interaction of apoA-V with lipoprotein lipase (Fig. ...
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... and VLDL, becoming one of the key components in the metabolism of TRLs [42]. The importance of apoC-II as an activator of lipoprotein lipase has been unequivocally demonstrated in patients with genetic defects in their structure or production and in transgenic animals [42,46]. ApoC-II is therefore required for maximal rates of TRL lipolysis [47] (Fig. 2). However, the mechanism whereby this protein ac- tivates lipoprotein lipase still remains elusive. For instance, it is under discussion whether apoC-II binds or not directly to lipoprotein lipase ...
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... along with the APOA1, APOA4, and APOA5 genes, belongs to a gene cluster that has been impli- cated as a potential genetic determinant for variations in triglycerides. Several lines of evidence involve apoC-III as a major player contributing to the development of hypertriglyceridemia [42,45,48]. First, apoC-III inhibits lipoprotein lipase activity (Fig. 2). Although the mechanism of this action is not yet understood, it may act by interfering with the bind- ing of lipoprotein lipase to lipids, which would result in a decreased ac- tivity and enhanced inactivation of the enzyme. Second, apoC-III also interferes with the binding of apoB-100 and apoE to hepatic receptors, leading to a ...
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... circulation, CMs acquire apoC-II, C-III, and E mainly from HDL and are subjected to triglyceride hydrolysis by lipoprotein lipase (Fig. 2). The function of this enzyme is modulated by apoC-II, which enhances the catalytic rate of the enzyme and is inhibited by apoC-III. During this hy- drolytic process, a substantial portion of phospholipid, apoAs, and Cs is removed from the delipidated TRLs and is transferred to the HDL ...
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... physiological importance of other determinants of CM clear- ance has been revealed from genetic defects in humans in recent years [65] (Fig. 2), including the lipase maturation factor (LMF) 1, glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1), and apoA-V. In addition, the hydrolysis of CM triglycerides originates remnant CMs, which are removed from circulation by the liver. This is, in part, due to the enrichment of these CM remnants ...
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... is a main determinant for postprandial lipemia [69]. This lipase is primarily produced by the parenchymal cells of adi- pose tissue, skeletal muscle, and myocardium. It is anchored to heparan sulfate chains (i.e., HSPGs) on the luminal surface of vascular endotheli- um, where it hydrolyzes the triglycerides of postprandial CMs and large VLDL (Fig. ...
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... function of lipoprotein lipase is modulated by several factors (depicted in Fig. 2). First, apoC-II enhances its action, while apoC-III is the endogenous inhibitor of this enzyme [8] (see Sections 1.3.6.2 and 1.3.6.3). Second, genetic mutations (see Section 3.1.1) have also re- vealed the physiological importance of the lipase maturation factor (LMF1), GPIHBP1, and apoA-V (encoded by APOA5) in regulating the ca- ...
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... it was first identified as an HDL binding protein, it directs the transendothelial transport of lipoprotein lipase to help anchor CMs to the endothelium. The acidic domain of GPIHBP1 ap- pears to be critical for lipoprotein lipase binding, since its replacement leads to an impaired ability of GPIHBP1 to bind both lipoprotein lipase and CMs (Fig. 2). Interestingly, mutations in the heparin-binding do- mains of both LPL and APOA5 abrogate the binding of these proteins to GPIHBP1. GPIHBP1 also prevents lipoprotein lipase inhibition by Angptl3 and Angptl4 [72], thereby providing another mechanism to preserve the lipoprotein lipase ...
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... and processing of lipoprotein lipase and hepatic lipase and, therefore, is critical for their function [65]. LMF1 is a membrane-bound protein that is localized in the lumen of endoplasmic reticulum. Although mutations in this gene are rare, they are associated with a reduced expression of both lipases in patients with severe hypertriglyceridemia (Fig. 2). The fact that the tissue distribution of LMF1 is not restricted only to the tis- sues synthesizing these two lipases suggests that LMF1 may exert broader biological ...
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... hyperchylomicronemia, is a rare disease with a prevalence of ~1 case in 1,000,000 inhabitants [89], char- acterized by the early onset of severe hypertriglyceridemia associated with chylomicronemia but without an increase in VLDL. It is mainly due to rare homozygous or double heterozygous, loss-of-function LPL gene variants (HLP1A, OMIM 238600) (Fig. 2). Also, mutations in sever- al additional loci, which encode for proteins involved in the activity, as- sembly, or transport of lipoprotein lipase, have been identified in patients with familial hyperchylomicronemia without LPL mutations. According to the OMIM database, less common causes of familial chylomicronemia (also represented in ...
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... (Fig. 2). Also, mutations in sever- al additional loci, which encode for proteins involved in the activity, as- sembly, or transport of lipoprotein lipase, have been identified in patients with familial hyperchylomicronemia without LPL mutations. According to the OMIM database, less common causes of familial chylomicronemia (also represented in Fig. 2), are rare, loss-of-function variants in APOC2 (HLP1B, OMIM 207750), GPIHBP1 (HLP1D, OMIM 615947), LMF1 (combined lipase deficiency, OMIM 246650), or APOA5 (late on-set hyperchylomicronemia, OMIM 144650), as well as the pres- ence in blood serum of circulating lipoprotein lipase inhibitors (HLP1C, OMIM 118830). However, in the latter, ...
Citations
... Their action is linked to the production of chylomicrons in the gut, which subsequently affect lipid absorption and metabolism [45,46]. ...
Background and aims
This study aimed to investigate the association between the Dietary Inflammatory Index (DII) and dyslipidemia, as well as to evaluate the mortality risk associated with DII in participants with dyslipidemia.
Methods
Data from the National Health and Nutrition Examination Survey database were divided into dyslipidemia and non-dyslipidemia groups. The association between DII and dyslipidemia was investigated using the weighted chi-square test, weighted t-test, and weighted logistic regression. Weighted Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals for all-cause and cardiovascular disease-related mortality within the dyslipidemia group.
Results
A total of 17,820 participants, including 4,839 without and 12,981 with dyslipidemia were analyzed in this study. The results showed that DII was higher in the dyslipidemia group compared to the non-dyslipidemia group (1.42 ± 0.03 vs. 1.23 ± 0.04, P < 0.01). However, for energy, protein, carbohydrates, total fat, saturated fat, and iron, DII was lower in participants with dyslipidemia. Logistic regression analysis revealed a strong positive association between DII and dyslipidemia. The odds ratios for dyslipidemia from Q1 to Q4 were 1.00 (reference), 1.12 (0.96–1.31), 1.23 (1.04–1.44), and 1.33 (1.11–1.59), respectively. In participants with dyslipidemia, a high DII was associated with high all-cause and cardiovascular mortality.
Conclusion
DII was closely associated with dyslipidemia. A pro-inflammatory diet may play a role in unfavorable consequences and is linked to both all-cause mortality and cardiovascular death in patients with dyslipidemia. Participants with dyslipidemia should pay attention to their anti-inflammatory dietary patterns.
... Lymphatics serve as a critical conduit for transporting dietary lipids from the gastrointestinal tract into systemic circulation. A typical route for intestinal fat absorption is the chylomicron pathway, which transports dietary lipids from enterocytes to lymphatics in the form of large triglyceriderich lipoprotein particles known as chylomicrons [281,282]. Another important route that allows particles such as pathogens to reach the intestinal lymphatics is the microfold cell (M cell) pathway. M cells are located within the intestinal epithelial layer in Peyer's patches, groups of mucosa-associated lymphoid follicles mainly found in the ileum [283,284]. ...
Recent advances in RNA sequencing technologies helped uncover what was once uncharted territory in the human genome-the complex and versatile world of long noncoding RNAs (lncRNAs). Previously thought of as merely transcriptional "noise", lncRNAs have now emerged as essential regulators of gene expression networks controlling development, homeostasis and disease progression. The regulatory functions of lncRNAs are broad and diverse, and the underlying molecular mechanisms are highly variable, acting at the transcriptional, post-transcriptional, translational, and post-translational levels. In recent years, evidence has accumulated to support the important role of lncRNAs in the development and functioning of the lymphatic vasculature and associated pathological processes such as tumor-induced lymphangiogenesis and cancer metastasis. In this review, we summarize the current knowledge on the role of lncRNAs in regulating the key genes and pathways involved in lymphatic vascular development and disease. Furthermore, we discuss the potential of lncRNAs as novel therapeutic targets and outline possible strategies for the development of lncRNA-based therapeutics to treat diseases of the lymphatic system.
... In addition, with appropriate sizes (less than 400 nm), liposomes can enter body compartments by two independent pathways: endocytotic and transendocytotic. Whereas the pathway from endosome to chylomicrons is complicated and time-consuming [44], transcytosis will result in intact liposomes crossing the intestine wall and rapidly entering the immunological system [27]. The latter will accelerate the appearance of cholecalciferol in serum and the subsequent transformation to calcidiol. ...
The changing environment and modified lifestyles have meant that many vitamins and minerals are deficient in a significant portion of the human population. Therefore, supplementation is a viable nutritional approach, which helps to maintain health and well-being. The supplementation efficiency of a highly hydrophobic compound such as cholecalciferol (logP > 7) depends predominantly on the formulation. To overcome difficulties associated with the evaluation of pharmacokinetics of cholecalciferol, a method based on the short time absorption data in the clinical study and physiologically based mathematical modeling is proposed. The method was used to compare pharmacokinetics of liposomal and oily formulations of vitamin D3. The liposomal formulation was more effective in elevating calcidiol concentration in serum. The determined AUC value for liposomal vitamin D3 formulation was four times bigger than that for the oily formulation.
... In the small intestine, dietary TG is decomposed into FA and monoglyceride or diglyceride before being absorbed by enterocytes. These decomposition products are reassembled into CM with cholesterol, phospholipids, and apoB48 (Julve et al., 2016;Santos-Baez and Ginsberg, 2020). Next, CMs are released into the lymphatic system and enter the circulation, where they obtain other apolipoproteins including apoCII, apoCIII, and apoE (Rosenson et al., 2014;Nakajima and Tanaka, 2018a). ...
Cardiovascular disease (CVD) is still the leading cause of death globally, and atherosclerosis is the main pathological basis of CVDs. Low-density lipoprotein cholesterol (LDL-C) is a strong causal factor of atherosclerosis. However, the first-line lipid-lowering drugs, statins, only reduce approximately 30% of the CVD risk. Of note, atherosclerotic CVD (ASCVD) cannot be eliminated in a great number of patients even their LDL-C levels meet the recommended clinical goals. Previously, whether the elevated plasma level of triglyceride is causally associated with ASCVD has been controversial. Recent genetic and epidemiological studies have demonstrated that triglyceride and triglyceride-rich lipoprotein (TGRL) are the main causal risk factors of the residual ASCVD. TGRLs and their metabolites can promote atherosclerosis via modulating inflammation, oxidative stress, and formation of foam cells. In this article, we will make a short review of TG and TGRL metabolism, display evidence of association between TG and ASCVD, summarize the atherogenic factors of TGRLs and their metabolites, and discuss the current findings and advances in TG-lowering therapies. This review provides information useful for the researchers in the field of CVD as well as for pharmacologists and clinicians.
... As shown in Figure 5, there were a significant increase in ApoB48 and ApoA-I outputs with the infusion of L-Gln. It is well established known that ApoB plays a critical role in the formation and secretion of intestinal chylomicron particles [49,50], and only one ApoB48 protein exists together with each chylomicron particle [51]. Considering the inconsistent result that increased ApoB output with no significant output of TG in our study, we speculated whether the size of particles was changed under L-Gln treatment. ...
Glutamine (Gln) is required for intestinal mucosal homeostasis, and it can promote triglyceride absorption. The intestinal mucosal mast cells (MMCs) are activated during fat absorption. This study investigated the potential role of Gln on fat absorption-induced activation of MMCs in rats. Lymph fistula rats (n = 24) were studied after an overnight recovery with the infusion of saline only, saline plus 85 mM L-glutamine (L-Gln) or 85 mM D-glutamine (D-Gln), respectively. On the test day, rats (n = 8/group) were given an intraduodenal bolus of 20% Intralipid contained either saline only (vehicle group), 85 mM L-Gln (L-Gln group), or 85 mM D-Gln (D-Gln group). Lymph was collected hourly for up to 6 h for analyses. The results showed that intestinal lymph from rats given L-Gln had increased levels of apolipoprotein B (ApoB) and A-I (ApoA-I), concomitant with an increased spectrum of smaller chylomicron particles. Unexpectedly, L-Gln also increased levels of rat mucosal mast cell protease II (RMCPII), as well as histamine and prostaglandin D2 (PGD2) in response to dietary lipid. However, these effects were not observed in rats treated with 85 mM of the stereoisomer D-Gln. Our results showed that L-glutamine could specifically activate MMCs to degranulate and release MMC mediators to the lymph during fat absorption. This observation is potentially important clinically since L-glutamine is often used to promote gut health and repair leaky gut.
... For highly hydrophobic compounds, such as vitamin D 3 , there are two potential pathways leading to the systemic circulation; transcytosis and chylomicron pathway. [35][36][37][38][39][40] The two pathways are qualitatively different; transcytosis allows vitamin D 3 to enter the circulation accompanied by a lipid carrier, while the chylomicron pathway requires a series of exchange events between proteins and lipid aggregates, before vitamin D 3 enters chylomicrons formed in the enterocyte cytoplasm. 41 The topological integrity of liposomes during digestion and absorption processes will likely affect vitamin D 3 bioavailability. ...
Vitamin D3 deficiency has serious health consequences, as demonstrated by its effect on severity and recovery after COVID-19 infection. Because of high hydrophobicity, its absorption and subsequent redistribution throughout the body are inherently dependent on the accompanying lipids and/or proteins. The effective oral vitamin D3 formulation should ensure penetration of the mucus layer followed by internalization by competent cells. Isothermal titration calorimetry and computer simulations show that vitamin D3 molecules cannot leave the hydrophobic environment, indicating that their absorption is predominantly driven by the digestion of the delivery vehicle. In the clinical experiment, liposomal vitamin D3 was compared to the oily formulation. The results obtained show that liposomal vitamin D3 causes a rapid increase in the plasma concentration of calcidiol. No such effect was observed when the oily formulation was used. The effect was especially pronounced for people with severe vitamin D3 deficiency.
... www.nature.com/nrcardio more than VLDL formation 24,70,73 . These LOF variants cause chylomicron retention disease, an autosomal reces sive disorder characterized by an inability to synthesize chylomicrons, which results in severe malabsorption and fatsoluble vitamin deficiency 70 . ...
... more than VLDL formation 24,70,73 . These LOF variants cause chylomicron retention disease, an autosomal reces sive disorder characterized by an inability to synthesize chylomicrons, which results in severe malabsorption and fatsoluble vitamin deficiency 70 . Genetic studies from the past 7 years have iden tified other proteins that are also important for TRL formation. ...
Accumulating evidence points to the causal role of triglyceride-rich lipoproteins and their cholesterol-enriched remnants in atherogenesis. Genetic studies in particular have not only revealed a relationship between plasma triglyceride levels and the risk of atherosclerotic cardiovascular disease, but have also identified key proteins responsible for the regulation of triglyceride transport. Kinetic studies in humans using stable isotope tracers have been especially useful in delineating the function of these proteins and revealing the hitherto unappreciated complexity of triglyceride-rich lipoprotein metabolism. Given that triglyceride is an essential energy source for mammals, triglyceride transport is regulated by numerous mechanisms that balance availability with the energy demands of the body. Ongoing investigations are focused on determining the consequences of dysregulation as a result of either dietary imprudence or genetic variation that increases the risk of atherosclerosis and pancreatitis. The identification of molecular control mechanisms involved in triglyceride metabolism has laid the groundwork for a 'precision-medicine' approach to therapy. Novel pharmacological agents under development have specific molecular targets within a regulatory framework, and their deployment heralds a new era in lipid-lowering-mediated prevention of disease. In this Review, we outline what is known about the dysregulation of triglyceride transport in human hypertriglyceridaemia.
... Lymphatics draining the intestine maintain intestinal fluid homeostasis and play a vital role in the transportation of macronutrients including dietary fats (triglycerides; TG), cholesterol (both free and esterified forms of cholesterol) and micronutrients such as fat-soluble vitamins: A, D, E, and K [1 && , [2][3][4]. Ingested lipids are absorbed by enterocytes and are either packaged into lipoprotein particles called chylomicrons (CM) or stored intracellularly as lipid droplets [3,5]. With progressive lipidation of nascent CM particles, CM are matured intracellularly and are secreted at the basolateral membrane of enterocytes into the lamina propria (LP) [5][6][7]. ...
... Lymphatics draining the intestine maintain intestinal fluid homeostasis and play a vital role in the transportation of macronutrients including dietary fats (triglycerides; TG), cholesterol (both free and esterified forms of cholesterol) and micronutrients such as fat-soluble vitamins: A, D, E, and K [1 && , [2][3][4]. Ingested lipids are absorbed by enterocytes and are either packaged into lipoprotein particles called chylomicrons (CM) or stored intracellularly as lipid droplets [3,5]. With progressive lipidation of nascent CM particles, CM are matured intracellularly and are secreted at the basolateral membrane of enterocytes into the lamina propria (LP) [5][6][7]. ...
... TG entering the intestine from the stomach are enzymatically hydrolyzed in the small intestine yielding FA and monoglycerides. These are absorbed by enterocytes and re-esterified to TG and form CM in the ER lumen and lipid droplets within the leaflets of the endoplasmic reticulum (ER) [3,5]. CM synthesis begins by lipidation of a lipid-poor apolipoprotein B48-containing particle facilitated by microsomal TG transfer protein to form pre-CMs [23 && , 24,25]. ...
Purpose of review:
Lymphatics are known to have active, regulated pumping by smooth muscle cells that enhance lymph flow, but whether active regulation of lymphatic pumping contributes significantly to the rate of appearance of chylomicrons (CMs) in the blood circulation (i.e., CM production rate) is not currently known. In this review, we highlight some of the potential mechanisms by which lymphatics may regulate CM production.
Recent findings:
Recent data from our lab and others are beginning to provide clues that suggest a more active role of lymphatics in regulating CM appearance in the circulation through various mechanisms. Potential contributors include apolipoproteins, glucose, glucagon-like peptide-2, and vascular endothelial growth factor-C, but there are likely to be many more.
Summary:
The digested products of dietary fats absorbed by the small intestine are re-esterified and packaged by enterocytes into large, triglyceride-rich CM particles or stored temporarily in intracellular cytoplasmic lipid droplets. Secreted CMs traverse the lamina propria and are transported via lymphatics and then the blood circulation to liver and extrahepatic tissues, where they are stored or metabolized as a rich energy source. Although indirect data suggest a relationship between lymphatic pumping and CM production, this concept requires more experimental evidence before we can be sure that lymphatic pumping contributes significantly to the rate of CM appearance in the blood circulation.
... This kind of assay could also be of clinical interest to improve HDL/LDL ratio measurements. In addition, PA probe was also sensitive to total Chol+TG levels, which in turn may also have further clinical interest as high levels of chylomicrons (TG carrier lipoprotein) are related to cardiovascular risk and/or acute pancreatitis [54]. ...
This work intends to describe the physical properties of red blood cell (RBC) membranes in obese adults. The hypothesis driving this research is that obesity, in addition to increasing the amount of body fat, will also modify the lipid composition of membranes in cells other than adipocytes. Forty-nine control volunteers (16 male, 33 female, BMI 21.8 ± 5.6 and 21.5 ±4.2 kg/m2, respectively) and 52 obese subjects (16 male and 36 female, BMI 38.2±11.0 and 40.7±8.7 kg/m2, respectively) were examined. The two physical techniques applied were atomic force microscopy (AFM) in the force spectroscopy mode, which allows the micromechanical measurement of penetration forces, and fluorescence anisotropy of trimethylammonium diphenylhexatriene (TMA-DPH), which provides information on lipid order at the membrane polar–nonpolar interface. These techniques, in combination with lipidomic studies, revealed a decreased rigidity in the interfacial region of the RBC membranes of obese as compared to control patients, related to parallel changes in lipid composition. Lipidomic data show an increase in the cholesterol/phospholipid mole ratio and a decrease in sphingomyelin contents in obese membranes. ω-3 fatty acids (e.g., docosahexaenoic acid) appear to be less prevalent in obese patient RBCs, and this is the case for both the global fatty acid distribution and for the individual major lipids in the membrane phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS). Moreover, some ω-6 fatty acids (e.g., arachidonic acid) are increased in obese patient RBCs. The switch from ω-3 to ω-6 lipids in obese subjects could be a major factor explaining the higher interfacial fluidity in obese patient RBC membranes.
... The assembly of chylomicrons is a highly complex multistep process, and less is still known about chylomicron assembly than VLDL assembly (Xiao et al. 2019;Hussain et al. 2005). However, it is known that in addition to MTTP, intestinal assembly of chylomicron requires Sar1 GTPase, which is critical for the intracellular transport of apoB48-containing particles from ER to the Golgi (Julve et al. 2016). The newly synthesized chylomicrons carrying dietary lipids and fat-soluble vitamins are secreted through lacteal endothelial gaps that are present in the postprandial phase into the venous system blood system through the lymphatic system. ...
... Chylomicron retention disease (CRD). In addition to MTP, chylomicron formation requires Sar1 GTPase, one of the subunits of the coat protein (COPII) complex, which is critical for the vesicular transport of apoB-48-containing particles from endoplasmic reticulum to the Golgi (Julve et al. 2016). Loss-of-function mutations in SAR1B, the gene encoding Sar1 homolog B GTPase causes CRD (also known as Anderson disease) (Julve et al. 2016), a rare autosomal-recessive disorder characterized by an intestinal defect in lipid transport due to a failure of chylomicron formation in enterocytes (Julve et al. 2016). ...
... In addition to MTP, chylomicron formation requires Sar1 GTPase, one of the subunits of the coat protein (COPII) complex, which is critical for the vesicular transport of apoB-48-containing particles from endoplasmic reticulum to the Golgi (Julve et al. 2016). Loss-of-function mutations in SAR1B, the gene encoding Sar1 homolog B GTPase causes CRD (also known as Anderson disease) (Julve et al. 2016), a rare autosomal-recessive disorder characterized by an intestinal defect in lipid transport due to a failure of chylomicron formation in enterocytes (Julve et al. 2016). ...
Triglycerides are critical lipids as they provide an energy source that is both compact and efficient. Due to its hydrophobic nature triglyceride molecules can pack together densely and so be stored in adipose tissue. To be transported in the aqueous medium of plasma, triglycerides have to be incorporated into lipoprotein particles along with other components such as cholesterol, phospholipid and associated structural and regulatory apolipoproteins. Here we discuss the physiology of normal triglyceride metabolism, and how impaired metabolism induces hypertriglyceridemia and its pathogenic consequences including atherosclerosis. We also discuss established and novel therapies to reduce triglyceride-rich lipoproteins.
