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Nutrient Modification of the Innate Immune Response A Novel Mechanism by Which Saturated Fatty Acids Greatly Amplify Monocyte Inflammation

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Nutrient Modification of the Innate Immune Response A Novel Mechanism by Which Saturated Fatty Acids Greatly Amplify Monocyte Inflammation

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Abstract

Monocyte/macrophage inflammation is an important contributor to diabetes and cardiovascular disease. Studies have suggested saturated fatty acids (SFA) induce monocyte inflammation in a Toll-like receptor-4-dependent manner, but recent data suggest SFA do not directly interact with Toll-like receptor-4. The present study tests the novel hypothesis that metabolism of SFA cooperatively amplifies Toll-like receptor-4-mediated inflammation. THP-1 monocytes exposed to 100 micromol/L SFA in vitro for 16 hours followed by 1 ng/mL lipopolysaccharide demonstrated enhanced IL-6 and IL-8 mRNA and protein expression (approximately 3-fold higher than the sum of individual responses to SFA and lipopolysaccharide). SFA had similar effects on THP-1 macrophages and primary human monocytes. This amplified lipopolysaccharide response could be blocked by inhibition of SFA metabolism to ceramide and restored by cell-permeable ceramide. Both SFA and ceramide activated PKC-zeta and the mitogen-activated protein kinases Erk, JNK, and p38. Inhibition of these pathways prevented the SFA-induced increase in cytokine expression. These results provide evidence for potent amplification of monocyte/macrophage innate immune responses by a novel pathway requiring metabolism of SFA to ceramide and activation of PKC-zeta/mitogen-activated protein kinases. These findings demonstrate how nutrient excess may modulate innate immune system activation and possibly contribute to development of diabetes and cardiovascular disease.

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... They can bind to the cell surface and intracellular receptors/sensors that control inflammatory cell signaling and gene expression. Several reports show a proinflammatory response in macrophages by SFAs depending on toll-like receptor activation (Chait and Kim, 2010;Schwartz et al., 2010;Shi et al., 2006;Snodgrass et al., 2013). The palmitic acid-mediated proinflammatory stimulation is associated with the activation of p38 and JNK kinases, inflammasome activation, and the NF-kB pathway (Haversen et al., 2009;Snodgrass et al., 2013;Suganami et al., 2007;Wen et al., 2011). ...
... SFAs are able to amplify the proinflammatory response of myeloid cells. Schwartz et al. (2010) describe, in addition to a direct proinflammatory effect of SFAs, an amplification of the LPS-induced proinflammatory response of monocytes by SFAs. Uptake of SFAs leads to enhanced ceramide generation, which in turn activates PKC-z and MAPK, resulting in increased IL-6 and IL-8 secretion upon LPS stimulation (Schwartz et al., 2010). ...
... Schwartz et al. (2010) describe, in addition to a direct proinflammatory effect of SFAs, an amplification of the LPS-induced proinflammatory response of monocytes by SFAs. Uptake of SFAs leads to enhanced ceramide generation, which in turn activates PKC-z and MAPK, resulting in increased IL-6 and IL-8 secretion upon LPS stimulation (Schwartz et al., 2010). Consistent with several studies, we observed an amplification of the proinflammatory response of myeloid cells by SFAs (Chang et al., 2012;Schwartz et al., 2010). ...
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In obesity, hypertrophic adipocytes secret high amounts of adipocytokines resulting in low-grade inflammation- amplified by infiltrating pro-inflammatory macrophages, oxidative stress, hypoxia and lipolysis. It is known, that these chronic pro-inflammatory conditions support the development of type II diabetes and cardio vascular diseases, while mechanisms of obesity-related exacerbation of inflammatory skin disorders like psoriasis are unclear. In this study, we uncover nutritional saturated fatty acids (SFAs) as major risk factors for the amplification of skin inflammation, independent of obesity-related parameters, like fat mass extension, adipocytokines and glucose homeostasis. Correlation analyses in a cohort of psoriasis vulgaris patients revealed free fatty acid (FFA)-serum-levels as the only obesity-associated parameter affecting disease severity. Studies in high fat diet-induced obese mice with psoriasiform inflammation confirmed this critical role of FFAs. Importantly, an increase of FFAs in healthy, lean mice alone was sufficient to induce an exacerbation of psoriasiform inflammation. In particular, SFAs sensitize myeloid cells to an increased inflammatory response in answer to pro-inflammatory stimuli which in turn augments the activation of keratinocytes. Consequently, reduction of nutritional SFAs alone diminished the psoriatic phenotype in obese mice. Thus, our findings may open new perspectives for adjuvant dietary measures accompanying anti-inflammatory psoriasis therapies in lean and obese patients.
... The murine macrophage-like cell line J774A.1 (abbreviated as J774) was from ATCC. We used J774 cells based on their reported use in evaluating the effects of mmLDL or mmLDL plus LPS [10,15]. Escherichia. ...
... In the co-treatment experiments, J774 cells that were untreated or treated palmitate for 16h were then treated with LPS with or without mmLDL for 30 min, 4h, or 6h (for immunoblotting, real time PCR, and ELISA, respectively). The methods used for this experiment were adapted from previous studies [10,14] Macrophages were treated first with palmitate and then with LPS in the former study, while the cells were treated with LPS and mmLDL together in the latter study. Taken together, we thought it was appropriate to treat the cells sequentially with palmitate and mmLDL when we evaluated any synergistic effect of these two agents. ...
... The present study has several limitations. First, there are additional pathways for palmitateor mmLDL-mediated effects that have been reported by others [10,14,15,35]. Although we have now identified novel genes and pathways that are regulated by the combined treatment with palmitate and mmLDL, the relative importance of these newly found genes and pathways compared to those that have been previously identified is uncertain. ...
Article
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Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-α secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL in the presence of lipopolysaccharide (LPS). Furthermore, the analysis of differentially expressed genes using the KEGG database revealed that several pathways, including cytokine-cytokine receptor interaction, and genes were significantly altered. These results were validated with real-time PCR, showing upregulation of Il-6, Csf3, Il-1β, and Clec4d. The present study demonstrated that palmitate and mmLDL additively potentiate the LPS-induced activation of macrophages. These results suggest the existence of synergistic mechanisms by which saturated fatty acids and oxidized lipoproteins activate immune cells.
... Increases in the glucose, FFA and pro-inflammatory cytokines secretion values in DM2 have been shown to have important implications for the immune system 88,89 . Studies in animal models and in humans have suggested a close link between DM2 and changes in innate immune system response 90 . ...
... Studies in animal models and in humans have suggested a close link between DM2 and changes in innate immune system response 90 . In this sense, Tolllike receptors (TLR), a family of transmembrane receptors that belong to the innate immune system and that recognize pathogen-associated molecular patterns, have an important participation in the pathogenesis of insulin resistance, inflammation and DM2 88,89,91 . In particular, TLR-4 have elevated expression and signaling in rodents and humans with obesity and insulin resistance, especially in insulin target tissues [91][92][93] . ...
... Consistently, several studies did not detect any direct FFA-mediated activation of myeloid cells (64,77,78). However, amplification of the pro-inflammatory response of myeloid cells in the presence of SFAs has been described in many studies (64,65,72,(77)(78)(79). How can SFAs amplify the pro-inflammatory response? ...
... Loss of PPAR-γ dampens de novo sterol biosynthesis and augments IFN-β production, which in turn suppresses the transcription of IL-1α and IL-1β in LPSstimulated macrophages (80). Uptake of SFAs leads to enhanced ceramide generation, which in turn activates PKC-ζ and MAPK, resulting in increased IL-6 and IL-8 secretion upon LPS stimulation (79). ...
Article
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Psoriasis is chronic inflammatory skin disease affecting skin, joints, cardiovascular system, brain, and metabolism. The pathogenesis of psoriasis is mediated by a complex interplay between the immune system, inflammatory mediators of different pathways, e.g., TNF-alpha and the IL-23/IL-17 pathways, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Psoriasis is triggered by the combination of genetic and environmental factors. A novel environmental risk factor with rising importance is obesity. Several studies proved that obesity is an independent risk factor for the onset and severity of psoriasis. Due to the dramatic increase of obesity worldwide this minireview focuses on obesity as a major environmental risk factor for psoriasis and the mechanisms of obesity-mediated exacerbation of psoriasis.
... Moreover, another publication demonstrated that ceramide can amplify the inflammatory response through a TLR4/LPS-independent mechanism. Indeed, saturated fatty acids (particularly palmitic acid) can be metabolized into ceramide that subsequently activates protein kinase C (PKC)zmediated signaling and results in amplification of TLR4-induced inflammation [109]. TNF-a and interleukin-1, pro-inflammatory cytokines secreted in response to TLR4, increase cellular ceramide content via sphingomyelin hydrolysis and de novo synthesis, respectively [10]. ...
... The same effects have been found in levels of transcripts encoding several enzymes involved in sphingolipid metabolism, especially ceramide biosynthesis, such SPT or CerS [106]. Of interest, ceramide may also activate pro-inflammatory pathways in macrophages via TLR4 [109,110], supporting a model in which ceramide can be both a cause and a result of macrophagemediated inflammation. ...
Article
Non-alcoholic fatty liver disease (NAFLD) involves a panel of pathologies starting with hepatic steatosis and continuing to irreversible and serious conditions like steatohepatitis (NASH) and hepatocarcinoma. NAFLD is multifactorial in origin and corresponds to abnormal fat deposition in liver. Even if triglycerides are mostly associated with these pathologies, other lipid moieties seem to be involved in the development and severity of NAFLD. That is the case with sphingolipids and more particularly ceramides. In this review, we explore the relationship between NAFLD and sphingolipid metabolism. After providing an analysis of complex sphingolipid metabolism, we focus on the potential involvement of sphingolipids in the different pathologies associated with NAFLD. An unbalanced ratio between ceramides and terminal metabolic products in the liver and plasma promotes weight gain, inflammation, and insulin resistance. In the etiology of NAFLD, some sphingolipid species such as ceramides may be potential biomarkers for NAFLD. We review the clinical relevance of sphingolipids in liver diseases.
... Moreover, saturated fatty acids (SFAs) stimulate TLR dimerization, leading to inflammation through the action of myeloid differentiation factor 88 (MyD88) (75). Further studies have shown that the mechanism of palmitic acid and stearic acid-mediated inflammation (to a lesser extent) is not directly linked to TLR4, but involves the conversion to ceramide under the activation of PKC, ERK1/2, JNK (stress-activated protein kinase, SAPK), and p38 (76). These ceramides then sensitize the downstream TLR4 to LPS, amplifying the inflammatory response (76). ...
... Further studies have shown that the mechanism of palmitic acid and stearic acid-mediated inflammation (to a lesser extent) is not directly linked to TLR4, but involves the conversion to ceramide under the activation of PKC, ERK1/2, JNK (stress-activated protein kinase, SAPK), and p38 (76). These ceramides then sensitize the downstream TLR4 to LPS, amplifying the inflammatory response (76). More interestingly, both ECs and vascular smooth muscle cells can oxidize LDL to some extent during culture, and this "minimally modified" LDL (mmLDL) in turn activates ECs to form a vicious circle by stimulating monocyte adhesion and migration (46). ...
Article
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Increasing attention is now being paid to the important role played by autophagic flux in maintaining normal blood vessel walls. Endothelial cell dysfunction initiates the development of atherosclerosis. In the endothelium, a variety of critical triggers ranging from shear stress to circulating blood lipids promote autophagy. Furthermore, emerging evidence links autophagy to a range of important physiological functions such as redox homeostasis, lipid metabolism, and the secretion of vasomodulatory substances that determine the life and death of endothelial cells. Thus, the promotion of autophagy in endothelial cells may have the potential for treating atherosclerosis. This paper reviews the role of endothelial cells in the pathogenesis of atherosclerosis and explores the molecular mechanisms involved in atherosclerosis development.
... Se ha demostrado que el incremento en los valores de glucosa, de AGL y de secreción de citocinas proinflamatorias en la DM2 tienen importantes implicaciones para el sistema inmunitario 88,89 . Estudios en modelos animales y en humanos han sugerido un vínculo estrecho entre la DM2 y los cambios en la respuesta del sistema inmunitario innato 90 . ...
... Estudios en modelos animales y en humanos han sugerido un vínculo estrecho entre la DM2 y los cambios en la respuesta del sistema inmunitario innato 90 . En este sentido, los receptores tipo Toll (TLR), una familia de receptores transmembrana que pertenecen al sistema inmunitario innato y que reconocen patrones moleculares asociados a patógenos, tienen una participación importante en la patogénesis de la resistencia a la insulina, la inflamación y la DM2 88,89,91 . En particular, los TLR-4 presentan una elevada expresión y señalización en roedores y humanos con obesidad y resistencia a la insulina, principalmente en tejidos diana de la insulina [91][92][93] . ...
Article
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Free fatty acids are essential nutritional components and recent studies identified them as signaling molecules in various physiological processes. It has now been shown that high levels of free fatty acids, particularly saturated fatty acids, may be associated with insulin resistance in obese patients with type 2 diabetes mellitus. Insulin resistance is important in clinical since it is related to various diseases including type 2 diabetes mellitus, dyslipidemia, and abnormalities at cardiovascular level. Recent studies have proposed different molecular mechanisms by which these lipids may alter the signaling pathway of insulin. The purpose of this review is to highlight recent advances in the study of the effect of free fatty acids as modulators of insulin response.
... Work in our laboratory showed that high physiological concentrations of SFA trigger the p38 mitogen activated protein kinase (MAPK) pathway and amplify the inflammatory response to low level lipopolysaccaride (LPS) exposure [6]. p38α MAPK signaling has also been implicated as being critical to programmed cell death of cardiomyocytes in many cardiomyopathies including the hypertrophic, doxorubicininduced, and amyloidogenic forms [2,[7][8][9][10][11]. ...
Article
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Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.
... Second, total even-chain SFA levels were positively associated with cardio-metabolic diseases potentially through all the tested pathways in this study, while individual even-chain SFAs appeared to have differential roles in these pathways. For example, only C16:0 was associated with the chronic inflammatory marker, CRP, in agreement with several in vitro studies [43][44][45]. The observed associations of evenchain SFAs with metabolic markers might partly reflect the effect of deregulation of de novo lipogenesis [46], as all of the three even-chain SFAs are within the de novo lipogenesis pathway, and these fatty acids were positively associated with risk of metabolic disorders [3,12]. ...
Article
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Background: Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine associations between plasma phospholipid SFAs and metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. Methods: We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0+C17:0, even-chain: C14:0+C16:0+C18:0 and very-long-chain: C20:0+C22:0+C23:0+C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across 8 European countries. Using linear regression in 15919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the 3 SFA groups with prespecified factors, including body-mass index (BMI) and alcohol consumption, were tested. Results: Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol [TC], triglycerides, apolipoprotein A-1 [ApoA1], apolipoprotein B [ApoB]) and hepatic markers (alanine transaminase [ALT], aspartate transaminase [AST], gamma-glutamyl transferase [GGT]). Higher even-chain SFA group levels were associated with higher levels of low-density-lipoprotein-cholesterol (LDL-C), TC/high-density-lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. Conclusions: Sub-types of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk, even-chain SFAs with adverse metabolic risk, and with mixed findings for very-long-chain SFAs. Clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.
... Elevated systemic inflammatory markers, such as high-sensitivity C-reactive protein (hsCRP), IL-6, and TNF-α, and vascular inflammatory markers, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, contribute to increased cardiometabolic risk (16,17). Although dietary total SFA has been positively associated with these inflammatory markers (18)(19)(20), there are extremely limited data on the relative effects of palmitic acid, stearic acid, and oleic acid on inflammatory mediators, and other cardiometabolic risk factors such as measures of immune cell function and coagulation. This missing information limits the attempts to refine dietary guidance and update Nutrient Facts labels, all of which may be undermining public health efforts aimed at reducing cardiometabolic risk through dietary modifications. ...
Article
Background: Direct comparisons between SFAs varying in chain length, specifically palmitic acid (16:0) and stearic acid (18:0), relative to the latter's metabolic product, oleic acid (18:1), on cardiometabolic risk factors are limited. Objective: The aim of this study was to determine the relative comparability of diets enriched in palmitic acid, stearic acid, and oleic acid on inflammation and coagulation markers, T lymphocyte proliferation/ex-vivo cytokine secretion, plasma cardiometabolic risk factors, and fecal bile acid concentrations. Methods: Hypercholesterolemic postmenopausal women (n = 20, mean ± SD age 64 ± 7 y, BMI 26.4 ± 3.4 kg/m2, LDL cholesterol ≥ 2.8 mmol/L) were provided with each of 3 diets [55% energy (%E) carbohydrate, 15%E protein, 30%E fat, with ∼50% fat contributed by palmitic acid, stearic acid, or oleic acid in each diet; 5 wk/diet phase] using a randomized crossover design with 2-wk washouts between phases. Outcome measures were assessed at the end of each phase. Results: Fasting LDL-cholesterol and non-HDL-cholesterol concentrations were lower after the stearic acid and oleic acid diets than the palmitic acid diet (all P < 0.01). Fasting HDL-cholesterol concentrations were lower after the stearic acid diet than the palmitic acid and oleic acid diets (P < 0.01). The stearic acid diet resulted in lower lithocholic acid (P = 0.01) and total secondary bile acid (SBA) concentrations (P = 0.04) than the oleic acid diet. All other outcome measures were similar between diets. Lithocholic acid concentrations were positively correlated with fasting LDL-cholesterol concentrations (r = 0.33; P = 0.011). Total SBA, lithocholic acid, and deoxycholic acid concentrations were negatively correlated with fasting HDL cholesterol (r = -0.51 to -0.44; P < 0.01) concentrations and positively correlated with LDL cholesterol:HDL cholesterol (r = 0.37-0.54; P < 0.01) ratios. Conclusions: Dietary stearic acid and oleic acid had similar effects on fasting LDL-cholesterol and non-HDL-cholesterol concentrations and more favorable ones than palmitic acid. Unlike oleic acid, the hypocholesterolemic effect of stearic acid may be mediated by inhibition of intestinal hydrophobic SBA synthesis. These findings add to the data suggesting there should be a reassessment of current SFA dietary guidance and Nutrient Facts panel labeling.This trial was registered at clinicaltrials.gov as NCT02145936.
... Although we did not observe any differences in the abilities between modified LDL and modified VLDL to induce inflammasome activation in lipopolysaccharide-primed macrophages, it can be speculated that the vast amounts of fatty acids produced by lipolysis of TGRLs are able to prime the cells more efficiently. In fact, Schwartz et al [90] have shown that saturated fatty acids can amplify inflammation by a pathway that requires metabolism of saturated fatty acids to ceramide. Interestingly, modification of VLDL by sphingomyelinase, which leads to generation of ceramide on the surface of the particles, also leads to substantial aggregation of the modified lipoproteins and formation of foam cells [55,56]. ...
Article
Apolipoprotein B -containing lipoproteins include triglyceride-rich lipoproteins (chylomicrons and their remnants, and very low density lipoproteins and their remnants) and cholesterol-rich low-density lipoprotein particles. Of these, lipoproteins having sizes below 70-80 nm may enter the arterial wall, where they accumulate and induce the formation of atherosclerotic lesions. The processes that lead to accumulation of lipoprotein-derived lipids in the arterial wall have been largely studied with focus on the low-density lipoprotein particles. However, recent observational and genetic studies have discovered that the triglyceride-rich lipoproteins and their remnants are linked with cardiovascular disease risk. In this review, we describe the potential mechanisms by which the triglyceride-rich remnant lipoproteins can contribute to the development of atherosclerotic lesions, and highlight the differences in the atherogenicity between low-density lipoproteins and the remnant lipoproteins.
... On the other hand, ceramides can aggravate inflammation in the liver. Ceramides have been shown to induce inflammation via activation of toll-like receptor 4 (TLR4) signaling pathway or NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3) inflammasome [99][100][101]. NLRP3 is a protein complex that mediates caspase-1 activation and secretion of the proinflammatory cytokines IL-1β and IL-18 [102]. In macrophages, ceramides activate the NLRP3 inflammasome and stimulate cytokine secretion [101]. ...
Article
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its advanced form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Ceramides have been shown to exacerbate NAFLD development through enhancing insulin resistance, reactive oxygen species production, liver steatosis, lipotoxicity and hepatocyte apoptosis, and eventually causing hepatic inflammation and fibrosis. Emerging evidence indicates that ceramide production in NAFLD is predominantly attributed to activation of the de novo synthesis pathway of ceramides in hepatocytes. More importantly, pharmacological modulation of ceramide de novo synthesis in preclinical studies seems efficacious for the treatment of NAFLD. In this review, we provide an overview of the pathogenic mechanisms of ceramides in NAFLD, discuss recent advances and challenges in pharmacological interventions targeting ceramide de novo synthesis, and propose some research directions in the field.
... Taken together, our in vivo and in vitro results indicate that NEFAs can induce the over-activation of the TLR-NF-κB pathway and promote the expression of IL-1β, IL-6, and TNF-α in PMNs. Increasing evidence has demonstrated that high concentrations of fatty acids, such as lauric acid, palmitic acid, or stearic acid [30], can activate TLR2 and TLR4 and induce inflammation effectively, which further supports our results. Dairy cows with clinical ketosis displayed high blood concentrations of NEFAs. ...
Article
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Background/aims: Dairy cows with clinical ketosis display a negative energy balance and high blood concentrations of non-esterified fatty acids (NEFAs), the latter of which is an important pathological factor of ketosis in cows. The aims of this study were to investigate the inflammatory status of ketotic cows and to determine whether and through what underlying mechanism high levels of NEFAs induce an inflammatory response. Methods: Proinflammatory factors and the nuclear factor kappa B (NF-κB) signaling pathway were evaluated in neutrophils from clinical ketotic and control cows, using methods including western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. In vitro, the effects of NEFAs on the NF-κB signaling pathway in cow neutrophils were also evaluated using the above experimental techniques. Results: Ketotic cows displayed low blood concentrations of glucose and high blood NEFA and β-hydroxybutyrate concentrations. Importantly, Toll-like receptor 2 (TLR2) and TLR4 expression and IκBα and NF-κB p65 phosphorylation levels in neutrophils (PMNs) were significantly higher in ketotic cows than in control cows, indicating over-activation of the TLR2/4-induced NF-κB inflammatory pathway in PMNs in ketotic cows. The blood concentrations of the inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were also significantly increased in ketotic cows. Interestingly, we found that NEFAs were positively correlated with proinflammatory cytokines. In vitro, after pharmacological inhibition of TLR2 and TLR4 expression in cow neutrophils, TLR2 and TLR4 expression was significantly decreased, and the phosphorylation level of NF-κB p65 was also reduced. Cow neutrophils were treated with different concentrations of NEFAs and pyrrolidine dithiocarbamate (PDTC; an NF-κB inhibitor). High concentrations of NEFAs (0.5 and 1 mM) significantly increased TLR2 and TLR4 expression, IκBα and NF-κB p65 phosphorylation levels, NF-κB p65 transcriptional activity, and IL-6, IL-1β, and TNF-α synthesis in cow neutrophils. The inhibition of NF-κB by PDTC suppressed the NEFA-induced synthesis of proinflammatory cytokines. Conclusions: High concentrations of NEFAs can over-activate the TLR2/4-mediated NF-κB signaling pathway to induce the over-production of proinflammatory cytokines, thereby increasing inflammation in cows with clinical ketosis.
... The cells were treated with the desired concentrations of CSP32 (17.6 and 88.0 μM) and l ng/mL LPS. A super-low dose of LPS (<1 ng/mL) is the physiologically relevant concentration that was used as a positive control [17,18]. After 24 h, the cells were incubated with 50 μg/mL MTT solution for 2 h, dissolved in dimethylsulfoxide (Sigma-Aldrich Chemical Co.), and then analyzed at 540 nm by a microplate reader (VERSA Max, Molecular Device Co., Sunnyvale, CA, USA). ...
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Antimicrobial peptides (AMPs) are components of the innate immune system and form the first defense against pathogens for various organisms. In the present study, we assessed whether CSP32, a novel AMP oligomer of bacitracin isolated from a strain of Bacillus spp., regulates the polarization of murine macrophage-like RAW 264.7 cells. CSP32 stimulated phagocytosis while inducing the appearance of the typical M1 polarized macrophage phenotype; these M1 macrophages play a role in host defense against pathogens. Furthermore, our results showed that CSP32 enhanced the expression and production of pro-inflammatory mediators, such as cytokines and chemokines. In addition, the CSP32-stimulated inflammatory mediators were induced mainly by the mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-κB) signaling pathway during M1 macrophage polarization. In particular, CSP32 markedly increased the numbers of Ca2+-positive macrophages while upregulating phospholipase C and activating protein kinase Cε. Furthermore, the inhibition of intracellular Ca2+ by BAPTA-AM, a Ca2+ chelator, significantly suppressed the CSP32-mediated phagocytosis, inflammatory mediator production, and NF-κB activation. In conclusion, our data suggested that CSP32-stimulated M1 macrophage polarization is dependent on the calcium signaling pathway and may result in enhanced immune capacities.
... The LPS was highly purified by phenol extraction and gel filtration chromatography and was cell-culture tested. PA (Sigma) used in this study was bovine serum albumin-free (40). To prepare PA, PA was dissolved in 0.1 N NaOH and 70% ethanol at 70°C to make PA solution at a concentration of 50 mM. ...
Article
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and consumption of high-fat diet (HFD) is a risk factor for NAFLD. The HFD not only increases intake of saturated fatty acid (SFA), but also induces metabolic endotoxemia, a HFD-associated increase in circulating lipopolysaccharide (LPS). Although it is known that SFA or LPS promotes hepatic inflammation, a hallmark of NAFLD, it remains unclear how SFA in combination with LPS stimulates host inflammatory response in hepatocytes. In this study, we performed both in vivo and in vitro experiments to investigate the effect of SFA in combination with LPS on proinflammatory gene expression in hepatocytes. Our animal study showed that feeding low-density lipoprotein-deficient mice HFD enriched with SFA and injection of low dose LPS cooperatively stimulated IL-6 expression in livers. To understand how SFA and LPS interact to promote IL-6 expression, our in vitro studies showed that palmitic acid (PA), a major SFA, and LPS exerted synergistic effect on the expression of IL-6 in hepatocytes. Furthermore, co-culture of hepatocytes with macrophages resulted in a greater IL-6 expression than culture of hepatocytes without macrophages in response to the combination of PA and LPS. Finally, we observed that LPS and PA increased ceramide production by cooperatively stimulating ceramide de novo synthesis, which played an essential role in the synergistic stimulation of proinflammatory gene expression by LPS and PA. Taken together, this study showed that SFA in combination with LPS stimulated a strong inflammatory response in hepatocytes in vivo and in vitro.
... There are several possible mechanisms whereby this could happen. First, metabolites of TGs, namely fatty acids and glycerides, could regulate inflammation (34)(35)(36)(37). Eicosanoids derived from fatty acid precursors such as prostaglandin E2, lipoxins LXA4, and LTB4 are known mediators of the inflammatory response in TB infection (38,39). ...
Article
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Pulmonary tuberculosis (TB) exhibits granulomatous inflammation, a site of controlling bacterial dissemination at the cost of host tissue damage. Intrigued by the granuloma type-dependent expression of inflammatory markers in TB, we sought to investigate underlying metabolic changes that drive amplification of inflammation in TB. Here, we show an association of higher inflammation in necrotic granulomas with the presence of triglyceride (TG)-rich foamy macrophages. The conspicuous absence of these macrophages in solid granulomas identified a link between the ensuing pathology and the metabolic programming of foamy macrophages. Consistent with in vivo findings, in vitro infection of macrophages with Mycobacterium tuberculosis (Mtb) led to increase in TG synthesis only under conditions of ~60% necrosis. Genetic and pharmacologic intervention that reduced necrosis prevented this bystander response. We further demonstrate that necrosis independent of Mtb also elicits the same bystander response in human macrophages. We identified a role for the human enzyme involved in TG synthesis, diacylglycerol O-acyltransferase (DGAT1), in this phenomenon. The increased TG levels in necrosis-associated foamy macrophages promoted the pro-inflammatory state of macrophages to infection while silencing expression of diacylglycerol O-acyltransferase (DGAT1) suppressed expression of pro-inflammatory genes. Our data thus invoke a role for storage lipids in the heightened host inflammatory response during infection-associated necrosis. Our data provide a functional role to macrophage lipid droplets in host defense and open new avenues for developing host-directed therapies against TB.
... Treating the cells with both palmitate and LPS synergistically induced the production of several pro-inflammatory cytokines. This finding is consistent with an earlier study reporting that palmitate amplifies the production of inflammatory cytokines (IL-6 and IL-8) upon LPS stimulation (Schwartz et al., 2010) of in human THP-1 monocytes. A similar observation was reported by Wen et al. (2011), who showed palmitate induction of IL-1b secretion in LPS primed macrophages. ...
... The relative expression levels of 40 mouse cytokines were determined in cell culture supernatant using a mouse cytokine array kit. In brief, RAW 264.7 cells were incubated with control media, 0.5, or 1.0 mg/mL GSH for 24 h, and LPS (1 ng/mL) was used as a positive control [23]. Following this, the supernatant was incubated on a nitrocellulose membrane containing 40 different cytokine antibodies for 1 h. ...
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The present study investigated the immunomodulatory activity of reduced glutathione (GSH) by assessment of the macrophage polarization (MP)-mediated immune response in RAW 264.7 cells. Furthermore, we identified the signal pathway associated with immune regulation by GSH. The expressions of MP-associated cytokines and chemokines were assessed using cytokine array, nCounter Sprit platform, ELISA and immunoblotting. Phagocytosis activity and intracellular reactive oxygen species (ROS) generation were measured using fluorescence-activated cell sorter. As results of the cytokine array and nCounter gene array, GSH not only up-regulated pro-inflammatory cytokines, including interleukins and tumor necrosis factor-α, but also overexpressed neutrophil-attracting chemokines. Furthermore, GSH significantly stimulated the production of immune mediators, including nitric oxide and PGE2, as well as phagocytosis activity through nuclear factor kappa B activation. In addition, GSH significantly decreased LPS-induced ROS generation, which was associated with an activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/ heme oxygenease-1 (HO-1) signaling pathway. Our results suggest that GSH has potential ROS scavenging capacity via the induction of Nrf2-mediated HO-1, and immune-enhancing activity by regulation of M1-like macrophage polarization, indicating that GSH may be a useful strategy to increase the human defense system.
... Smaller previous studies have reported a positive association between circulating MUFAs and SFAs and stroke risk, [32][33][34] which were mostly not confirmed by our findings, although there was some evidence for a positive association between MUFAs and stroke risk after accounting for other fatty acids. Fatty acids are dynamic molecules capable of influencing a wide range of cell signaling pathways and potentially modulating lipid metabolism, 4,42,43 glucose homeostasis, 44,45 blood pressure, [46][47][48] inflammatory response, [49][50][51] and endothelial function. 48,52 The circulating fatty acids pool reflects the dynamic contribution of multiple metabolic pathways regulated by key hormonal signals, including adipose tissue lipolysis (the main source of free circulating fatty acids during fasting), hydrolysis of blood triglycerides in triglyceride-rich lipoproteins, reesterification to triglycerides within adipocytes, and peripheral fatty acids utilization. ...
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Background We aimed at investigating the association of circulating fatty acids with coronary heart disease ( CHD ) and stroke risk. Methods and Results We conducted an individual‐participant data meta‐analysis of 5 UK ‐based cohorts and 1 matched case‐control study. Fatty acids (ie, omega‐3 docosahexaenoic acid, omega‐6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high‐throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI , 0.76–0.95 per standard unit of docosahexaenoic acid), there was evidence of high between‐study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI , 0.75–0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI , 1.03–1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI , 0.82–1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD . The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.
... Treating the cells with both palmitate and LPS synergistically induced the production of several pro-inflammatory cytokines. This finding is consistent with an earlier study reporting that palmitate amplifies the production of inflammatory cytokines (IL-6 and IL-8) upon LPS stimulation (Schwartz et al., 2010) of in human THP-1 monocytes. A similar observation was reported by Wen et al. (2011), who showed palmitate induction of IL-1β secretion in LPS primed macrophages. ...
Article
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The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors.
... Additionally, pro-inflammatory cytokines, including TNF-α, IL-1β, IL-18, IL-6 and IL-17, are main factors causing inflammatory response, and their activation is a key to accelerate disease progression (52). In this study, we found that LPS induced higher expression of these pro-inflammatory cytokines, was in line with a previous report in acute lung injury caused by LPS (53,54). However, ST1926 showed significantly suppressive role in controlling the cytokine secretion, inhibiting inflammation. ...
Article
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Bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been well developed and investigated in clinical trials for many diseases. The aim of our study was to explore the role of ST1926 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to reveal the possible molecular mechanism. Mice were treated with LPS to induce acute lung injury followed by ST1926 administration. After LPS induction, mice administered with ST1926 showed lower inflammation infiltration in bronchoalveolar lavage (BAL) fluid, and pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-18, IL-6 and tumor necrosis factor-α (TNF-α) in serum and lung tissue samples obtained from mice. In addition, western blot assays suggested that ST1926 suppressed nuclear factor-κB (NF-κB), inhibitor-κB kinase-α (IκBα) and IκB kinase (IKKα), as well as Toll-like receptor 4 (TLR4) induced by LPS. In addition, reactive oxygen species (ROS) stimulated by LPS was also suppressed for ST1926 through inhibiting p38 and extracellular receptor kinase (ERK) signaling pathway. Taken together, the data here indicated that ST1926 may be of potential value in treating acute lung injury through inflammation and ROS suppression via inactivating TLR4/NF-κB and p38/ERK1/2 signaling pathways.
... The modern dietary pattern tends to contain high fat and low fiber. The excessive intake of food containing saturated fatty acid (SFA) may become the precursor for proinflammatory indicator modulation and might worsen the disease severity [35]. Nutrients that are involved in antioxidant and antiinflammatory production include, vitamin A, vitamin C, omega-3-fatty acid, polyphenols, and carotenoids from a plant-based diet. ...
Article
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In the ongoing coronavirus disease 19 (COVID-19) pandemic, the most vulnerable groups are those with pre-existing health problems and the elderly due to their reduced immune system to prevent infection. Nutrition plays a significant role in maintaining the immune system to prevent pathogen manifestation. This review aimed to identify and discuss the role of nutrients in COVID-19 in developing immunity. Studies included in this review were obtained from articles published in reputable journals accessed from the National Center for Biotechnology Information (NCBI) website, leading search engine, in a retrospective timeframe from January 1 to May 2, 2020, using specified keywords. The search resulted in seven articles relevant to the objective of the review. They highlighted the role of nutrients, namely the deficiency of essential nutrients that might exacerbate the health status. The consumption of certain nutrients, micronutrient and omega-3 might be tolerated up to the upper level of recommended dietary allowance (RDA) to benefit the health status. This review can assist in providing the prevention and mitigation approach to improve immunity amid the COVID-19 pandemic. The government should expand the continuous delivery of messages regarding the benefit of appropriate nutrients in maintaining health and immune system. Furthermore, the current condition gives the best opportunity to educate the community on a healthy and balanced diet for daily life.
... These compounds are able to activate Toll-like receptor-4 (TLR4) signaling [102], a member of the family of Toll-like receptors which, after recognizing exogenous pathogen-associated molecular components and various non-microbial damage-associated molecular patterns, promote the synthesis of pro-inflammatory cytokines and chemokines and induce the expression of co-stimulatory molecules, such as CD80 (cluster of differentiation) and CD86, on antigen-presenting dendritic cells, thus triggering adaptive immune responses [102]. Furthermore, SFAs might amplify inflammation through the increased synthesis of ceramides (bioactive sphingolipids mediating numerous cell-signaling events), which enhance the NF-κB pathway, thus increasing the expression of several pro-inflammatory genes [103,104]. Finally, SFAs might contribute to low-grade systemic inflammation by modulating the gut microbiota composition. High SFA diets have been implicated in reducing the gut microbiota richness, increasing the Firmicutes-to-Bacteroidetes ratio, and inducing gut dysbiosis [105,106]. ...
Article
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The aim of this observational study was investigating the possible correlation between adherence to the Mediterranean diet (MeD) and SARS-COV-2 infection rates and severity among healthcare professionals (HCPs). An online self-administrated questionnaire (evaluating both MeD adherence and dietary habits) was filled out by HCPs working in Piedmont (Northern Italy) from 15 January to 28 February 2021. Out of the 1206 questionnaires collected, 900 were considered reliable and analyzed. Individuals who reported the SARS-COV-2 infection (n = 148) showed a significantly lower MeD score, with a lower adherence in fruit, vegetables, cereals, and olive oil consumption. In a logistic regression model, the risk of infection was inversely associated with the MeD score (OR = 0.88; 95% CI 0.81–0.97) and the consumption of cereals (OR = 0.64; 0.45–0.90). Asymptomatic individuals with SARS-COV-2 infection reported a lower intake of saturated fats than symptomatic; individuals requiring hospitalization were significantly older and reported worse dietary habits than both asymptomatic and symptomatic individuals. After combining all symptomatic individuals together, age (OR = 1.05; 1.01–1.09) and saturated fats intake (OR = 1.09; 1.01–1.17) were associated with the infection severity. HCPs who reported a SARS-COV-2 infection showed a significantly lower MeD score and cereal consumption. The infection severity was directly associated with higher age and saturated fat intake.
... These are the major saturated and monounsaturated fatty acids (MUFA) produced by the de novo lipogenesis (DNL) pathway [21]. Experimental studies have demonstrated that palmitic acid induces endoplasmic reticulum stress, cellular apoptosis and activates pro-inflammatory pathways [22][23][24]. Thus, this decrease in DNL species reinforces the idea that statins achieve some of their beneficial effects through modulation of fatty acid metabolism. ...
Article
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Statins are the first-line lipid-lowering therapy for reducing cardiovascular disease (CVD) risk. A plasma lipid ratio of two phospholipids, PI(36:2) and PC(18:0_20:4), was previously identified to explain 58% of the relative CVD risk reduction associated with pravastatin, independent of a change in low-density lipoprotein-cholesterol. This ratio may be a potential biomarker for the treatment effect of statins; however, the underlying mechanisms linking this ratio to CVD risk remain unclear. In this study, we investigated the effect of altered cholesterol conditions on the lipidome of cultured human liver cells (Hep3B). Hep3B cells were treated with simvastatin (5 μM), cyclodextrin (20 mg/mL) or cholesterol-loaded cyclodextrin (20 mg/mL) for 48 hours and their lipidomes were examined. Induction of a low-cholesterol environment via simvastatin or cyclodextrin was associated with elevated levels of lipids containing arachidonic acid and decreases in phosphatidylinositol species and the PI(36:2)/PC(18:0_20:4) ratio. Conversely, increasing cholesterol levels via cholesterol-loaded cyclodextrin resulted in reciprocal regulation of these lipid parameters. Expression of genes involved in cholesterol and fatty acid synthesis supported the lipidomics data. These findings demonstrate that the PI(36:2)/PC(18:0_20:4) ratio responds to changes in intracellular cholesterol abundance per se, likely through a flux of the n-6 fatty acid pathway and altered phosphatidylinositol synthesis. These findings support this ratio as a potential marker for CVD risk reduction and may be useful in monitoring treatment response.
... Im Einklang mit den vorliegenden Daten erwähnte eine Studie, dass Palmitat in U937-Monozyten, im Gegensatz zu RAW 264.7-Makrophagen, nicht die LPS-induzierte Entzündungsantwort verstärkte [66].Alles in allem spricht die mangelhafte Datenlage dafür, dass Palmitat in U937-Zellen, im Gegensatz zu den meisten anderen Monozyten-bzw. Makrophagen-Zellkulturmodellen[135,137,150,166,247], keine Entzündungsantwort auslöst. Unklar ist, worauf dies zurückzuführen ist. ...
Thesis
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Insulinresistenz ist ein zentraler Bestandteil des metabolischen Syndroms und trägt maßgeblich zur Ausbildung eines Typ-2-Diabetes bei. Eine mögliche Ursache für die Entstehung von Insulinresistenz ist eine chronische unterschwellige Entzündung, welche ihren Ursprung im Fettgewebe übergewichtiger Personen hat. Eingewanderte Makrophagen produzieren vermehrt pro-inflammatorische Mediatoren, wie Zytokine und Prostaglandine, wodurch die Konzentrationen dieser Substanzen sowohl lokal als auch systemisch erhöht sind. Darüber hinaus weisen übergewichtige Personen einen gestörten Fettsäuremetabolismus und eine erhöhte Darmpermeabilität auf. Ein gesteigerter Flux an freien Fettsäuren vom Fettgewebe in andere Organe führt zu einer lokalen Konzentrationssteigerung in diesen Organen. Eine erhöhte Darmpermeabilität erleichtert das Eindringen von Pathogenen und anderer körperfremder Substanzen in den Körper. Ziel dieser Arbeit war es, zu untersuchen, ob hohe Konzentrationen von Insulin, des bakteriellen Bestandteils Lipopolysaccharid (LPS) oder der freien Fettsäure Palmitat eine Entzündungsreaktion in Makrophagen auslösen oder verstärken können und ob diese Entzündungsantwort zur Ausbildung einer Insulinresistenz beitragen kann. Weiterhin sollte untersucht werden, ob Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind, die Produktion des Prostaglandins (PG) E2 begünstigen können und ob dieses wiederum die Entzündungsreaktion und seine eigene Produktion in Makrophagen regulieren kann. Um den Einfluss dieser Faktoren auf die Produktion pro-inflammatorischer Mediatoren in Makrophagen zu untersuchen, wurden Monozyten-artigen Zelllinien und primäre humane Monozyten, welche aus dem Blut gesunder Probanden isoliert wurden, in Makrophagen differenziert und mit Insulin, LPS, Palmitat und/ oder PGE2 inkubiert. Überdies wurden primäre Hepatozyten der Ratte isoliert und mit Überständen Insulin-stimulierter Makrophagen inkubiert, um zu untersuchen, ob die Entzündungsanwort in Makrophagen an der Ausbildung einer Insulinresistenz in Hepatozyten beteiligt ist. Insulin induzierte die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien wahrscheinlich vorrangig über den Phosphoinositid-3-Kinase (PI3K)-Akt-Signalweg mit anschließender Aktiverung des Transkriptionsfaktors NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells). Die dabei ausgeschütteten Zytokine hemmten in primären Hepatozyten der Ratte die Insulin-induzierte Expression der Glukokinase durch Überstände Insulin-stimulierter Makrophagen. Auch LPS oder Palmitat, deren lokale Konzentrationen im Zuge des metabolischen Syndroms erhöht sind, waren in der Lage, die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien zu stimulieren. Während LPS seine Wirkung, laut Literatur, unbestritten über eine Aktivierung des Toll-ähnlichen Rezeptors (toll-like receptor; TLR) 4 vermittelt, scheint Palmitat jedoch weitestgehend TLR4-unabhängig wirken zu können. Vielmehr schien die de novo-Ceramidsynthese eine entscheidene Rolle zu spielen. Darüber hinaus verstärkte Insulin sowohl die LPS- als auch die Palmitat-induzierte Ent-zündungsantwort in beiden Zelllinien. Die in Zelllinien gewonnenen Ergebnisse wurden größtenteils in primären humanen Makrophagen bestätigt. Desweiteren induzierten sowohl Insulin als auch LPS oder Palmitat die Produktion von PGE2 in den untersuchten Makrophagen. Die Daten legen nahe, dass dies auf eine gesteigerte Expression PGE2-synthetisierender Enzyme zurückzuführen ist. PGE2 wiederum hemmte auf der einen Seite die Stimulus-abhängige Expression des pro-inflammatorischen Zytokins Tumornekrosefaktor (TNF) α in U937-Makrophagen. Auf der anderen Seite verstärkte es jedoch die Expression der pro-inflammatorischen Zytokine Interleukin- (IL-) 1β und IL-8. Darüber hinaus verstärkte es die Expression von IL-6-Typ-Zytokinen, welche sowohl pro- als auch anti-inflammatorisch wirken können. Außerdem vestärkte PGE2 die Expression PGE2-synthetisierender Enzyme. Es scheint daher in der Lage zu sein, seine eigene Synthese zu verstärken. Zusammenfassend kann die Freisetzung pro-inflammatorischer Mediatoren aus Makro-phagen im Zuge einer Hyperinsulinämie die Entstehung einer Insulinresistenz begünstigen. Insulin ist daher in der Lage, einen Teufelskreis der immer stärker werdenden Insulin-resistenz in Gang zu setzen. Auch Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind (zum Beispiel LPS, freie Fettsäuren und PGE2), lösten Entzündungsantworten in Makrophagen aus. Das wechselseitige Zusammenspiel von Insulin und diesen Metaboliten und Signalsubstanzen löste eine stärkere Entzündungsantwort in Makrophagen aus als jeder der Einzelkomponenten. Die dadurch freigesetzten Zytokine könnten zur Manifestation einer Insulinresistenz und des metabolischen Syndroms beitragen.
... The PA, DHA, eicosapentaenoic acid (EPA), oleic acid (OA), linoleic acid (LA) and palmitoleic acid (POA) used in this study were purchased from Sigma (St. Louis, MO) and prepared as described previously [20,21]. Briefly, fatty acids were dissolved in 0.1 N NaOH and 70% ethanol at 70˚C to make concentration of 50 mM. ...
Article
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It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages.
... Palmitic Acid and Trained Immunity: Palmitic acid (PA) is a long-chain saturated fatty acid that is found in diets enriched in animal fats including meat, milk, and butter, (Carta, et al., 2017). Many groups have shown that PA can induce inflammation in macrophages and monocytes, (Napier et al., 2019, Korbecki, et al. 2019, Laine, et al., 2007, Tzeng, et al., 2019, Schwartz, et al., 2010. ...
... It suggested that although the chronic hepatitis occurred in sucrose overfeeding group, the hepatocyte was not seriously injured and the liver function was not affected, which showed that the inflammation inhibition mechanism existed in goose liver (Geng et al., 2016a). It has been reported that the unsaturated fatty acids (UFA) could inhibit SFA-induced elevation of ceramides and inflammation (Schwartz et al., 2010). The fatty liver of goose is more common in UFA when compared to the mammalian fatty liver, with the polyunsaturated fatty acids in particular, such as omega-3 and omega-6 (Tang et al., 2018), that is, the content of SFA is 39 to 47% in the fatty liver of overfed goose (Allard et al., 2008); the content of SFA is 52 to 56% in the liver of human suffered from NAFD (Molette et al., 2001). ...
Article
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Early research in our lab indicated that the effect of glucose, fructose and sucrose on the levels of triacylglycerol and inflammatory factor was significantly different, and it is speculated that the regulatory mechanism of lipid deposition by different type of sugar in the liver is different. In order to explore lipid deposition difference mediated by different types of sugar (glucose, fructose and sucrose) in goose fatty liver formation, this experiment was performed from cell culture, overfeeding experiment and transcriptome analysis three level. Cell culture experiment results indicated that the levels of intracellular triglyceride, total cholesterol and lipid content of fructose and sucrose treatment were significantly higher than those of glucose treatment (P < 0.05). In slaughter performance, the liver weight, the ratio of liver weight to body weight, feed conversion ratio (liver weight / feed consumption) were better in sucrose overfeeding group (P < 0.05). In addition, the liver of the sucrose overfeeding group contained a lot of unsaturated fatty acids, especially (n-3) polyunsaturated fatty acids (P < 0.05). Transcriptome analysis shown that the peroxisome proliferators-activated receptor (PPAR) signaling pathway is highly enriched in the fructose and sucrose overfeeding groups; cell cycle and DNA replication pathways were highly enriched in the glucose overfeeding group. In conclusion, due to the decrease of lipids outward transportation and the anti-inflammation of unsaturated fatty acids, fructose and sucrose have better ability to induce steatosis in goose fatty liver formation.
... Another mechanism that links saturated fatty acids to inflammation is that they can be used to form ceramides, which when incorporated into plasma membranes form lipid rafts that are unique in their biophysical properties and are involved in the activation of signaling pathways associated with inflammation and apoptosis [66]. For example, palmitic acid has been shown to induce sphingomyelin hydrolysis mediated by neutral sphingomyelinase (nSMase), which is involved in IL-6 activation [67]. ...
Article
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Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is associated with the accumulation of lipids in the arterial intima and the disruption of mechanisms that maintain the balance between the development and resolution of inflammation. Fatty acids are involved in many mechanisms of inflammation development and maintenance. Endothelial cells demonstrate multiple cross-linkages between lipid metabolism and innate immunity. In addition, these processes are linked to hemodynamics and the function of other cells in the vascular wall, highlighting the central role of the endothelium in vascular biology.
... factors and peroxisome proliferator-activated receptors (PPARs) [34] and by stimulating the expression of pro-inflammatory cytokines and chemokines, such as TNF-a, IL-6 and MCP-1 [35]. SFA have been associated with major effects on inflammation, including activation of monocytes and oxygen radical production and on vascular endothelial cells [36]. ...
... It suggested that although the chronic hepatitis occurred in sucrose overfeeding group, the hepatocyte was not seriously injured and the liver function was not affected, which showed that the in ammation inhibition mechanism existed in goose liver [44]. It has been reported that the unsaturated fatty acids (UFA) could inhibit SFA-induced elevation of ceramides and in ammation [45]. The fatty liver of goose is more common in UFA when compared to the mammalian fatty liver, with the polyunsaturated fatty acids in particular, such as omega-3 and omega-6 [46], i.e., the content of SFA is 39-47% in the fatty liver of overfed goose [47]; the content of SFA is 52-56% in the liver of human suffered from NAFD [48]. ...
Preprint
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Backgroud: Early research in our lab is indicated that the effect of glucose, fructose and sucrose on the levels of triacylglycerol and inflammatory factor was significantly different, and it is speculated that the regulatory mechanism of lipid deposition by different type of sugar in the liver is different. Methods: In order to explore lipid deposition difference mediated by different type of sugar (glucos, fructose and sucrose) in goose fatty liver formation, this experiment was performed from cell culture, overfeeding experiment and transcriptome analysis three level. Results: Cell culture experiment results indicated that the levels of intracellular triglyceride (TG), total cholesterol (T-CHO) and lipid content of fructose treatment and sucrose treatment were significantly higher than those of glucose treatment (P < 0.05). In slaughter performance, the liver weight, the ratio of liver weight to body weight, feed conversion ratio (liver weight / feed consumption ) were better in sucrose overfeeding group (P < 0.05). In addition, the liver of the sucrose overfeeding group contained a lot of unsaturated fatty acids, especially (n-3) polyunsaturated fatty acids (n-3 PUFA ) (P < 0.05). Transcriptome analysis shown that the PPAR signaling pathway is highly enriched in the fructose and sucrose overfeeding groups; cell cycle and DNA replication pathways were highly enriched in the glucose overfeeding group. Conclusions: Due to lipids outward transportation decrease and anti-imflammation of unsaturated fatty acids (UFA), thereby, fructose and sucrose hve better ability to induce steatosis in foie gras formation.
Thesis
Während der normalen Schwangerschaft entwickelt sich im mütterlichen Stoffwechsel ein atherogenes Lipidprofil, um den wachsenden Fötus adäquat zu versorgen. Patientinnen mit Präeklampsie zeigen darüber hinausgehende Veränderungen im Lipidstoffwechsel: Insbesondere triglyceridreiche Lipoproteine und freie Fettsäuren sind zusätzlich erhöht. Verschiedene Lipidspezies beeinflussen die Endothelfunktion negativ und sind möglicherweise an der Entstehung der mütterlichen endothelialen Dysfunktion bei der Präeklampsie beteiligt. In der vorliegenden Arbeit wurde der Effekt einer Lipidapherese mittels H.E.L.P.-Verfahren (Heparin-induzierte extrakorporale LDL-Präzipitation) auf das Lipidprofil in 7 Patientinnen mit Präeklampsie untersucht. Das Lipoproteinprofil nach Apherese unterschied sich deutlich von dem theoretisch zu erwartenden Profil. Zudem war der Wiederanstieg der Lipide nach der Apherese beschleunigt. Diese Änderungen deuten auf eine deutlich erhöhte Umsatzrate von ApoB-haltigen Lipoproteinen hin. Auch die Komposition der einzelnen Lipidklassen veränderte sich, wobei in der Gesamtbilanz die Triglyceridmenge nach Apherese größer war als rechnerisch zu erwarten. Dies weist darauf hin, dass aus einem zusätzlichen Kompartiment Triglyceride in den Lipoproteinpool einfließen und unterstreicht die Bedeutung der Triglyceride im veränderten Lipidprofil bei Präeklampsie. Der Einfluss von Lipiden auf die Aktivität verschiedener an der Regulation des Blutdruckes beteiligter G-Protein gekoppelter Rezeptoren (GPCR) wurde über die fluoreszenzspektrometrische Bestimmung der Kalziumfreisetzung in Zellkulturmodellen untersucht. Während der Angiotensin-Rezeptor keine lipidabhängige Änderung der Signalintensität zeigte, reagierten der Bradykinin- und Endothelin-Rezeptor auf einen steigenden Gehalt an Triglyceriden (vor allem bei Very low-density Lipoproteinen (VLDL) und Intermediate-density Lipoproteinen (IDL)) mit einer signifikanten Verringerung ihrer Aktivität. Die endotheliale Dysfunktion bei der Präeklampsie wird somit möglicherweise von triglyceridreichen Lipoproteinen beeinflusst. Darüber hinaus bewirkte die langkettige Fettsäure C18:0 eine Verringerung der Aktivität des Bradykinin- und Endothelin-Rezeptors, während die analoge einfach ungesättigte Fettsäure C18:1 keinen Effekt zeigte. Neben der Quantität der entsprechenden Lipidklassen ist folglich auch die chemische Struktur der beteiligten Lipide für die Funktionalität der entsprechenden GPCR von Bedeutung.
Thesis
L'athérosclérose est une pathologie causée par des remaniements de l'intima des artères de gros et moyencalibre. Ils se manifestent par une accumulation locale de lipides, de glucides complexes, de sang et deproduits sanguins, de tissu fibreux et de dépôt calcaires, et s'accompagnent de modifications de la media.L'athérosclérose est à l'origine d'une grande partie des pathologies cardiovasculaires causées par laprésence des plaques d'athérome dont la rupture entraine des complications thrombo-emboliques.De nombreux facteurs de risque cardiovasculaires ont été identifiés, mais des incertitudes demeurentquant aux mécanismes impliqués dans le développement de l'athérosclérose et de ses complications.Certains facteurs de risques, reconnus par la Haute autorité de santé, servent à évaluer le risquecardiovasculaire. D'autres, émergents ou peu fiables, ne sont pas utilisés en routine par les praticiens.Plusieurs études épidémiologiques attribuent à l'environnement une part importante dans ledéveloppement de l'athérosclérose. L'alimentation est mise en avant dans la quasi-totalité de ces études.Des recherches ont été conduites dans le domaine de la nutrition, dans le but d'établir un modèlealimentaire adéquat pour la prévention des maladies cardiovasculaires. L'analyse indépendante desconstituants de l'alimentation révèle le caractère nocif d'un excès d'acides gras trans, d'acides grassaturés à longue chaîne, de glucides entraînant une charge glycémique élevée, de fructose, et d'alcool.Sont également nocifs un déficit d'acides gras oméga 3 par rapport aux acides gras omégas 6, un déficiten certains minéraux et vitamines. Par contre, certains éléments non essentiels au métabolisme protègentdu risque cardiovasculaire : fibres, polyphénols, et alcool (en quantité inférieure à 72 grammes par jour).L'étude des régimes alimentaires de populations à faible risque cardiovasculaire (Okinawaienne,méditerranéenne, Esquimaude...) concordent avec les observations précédentes. Elle a conduit àreconnaître que le régime dit méditerranéen est un régime alimentaire protecteur du risquecardiovasculaire aisément applicable en France. Le programme national nutrition santé (PNNS) s'en estd'ailleurs fortement inspiré et les recommandations de ce programme peuvent servir de modèle globalpour une nutrition favorisant une bonne santé cardiovasculaire.
Article
A high-fat diet induces hypothalamic inflammation in rodents which, in turn, contributes to the development of obesity by eliciting both insulin and leptin resistance. However, the mechanism by which long-chain saturated fatty acids trigger inflammation is still contentious. To elucidate this mechanism, the effect of fatty acids on the expression of the pro-inflammatory cytokines IL-6 and TNFα was investigated in the mHypoE-N42 hypothalamic cell line (N42). N42 cells were treated with lauric acid (LA) and palmitic acid (PA). PA challenge was carried out in the presence of either a TLR4 inhibitor, a ceramide synthesis inhibitor (L-cycloserine), oleic acid (OA) or eicosapentaenoic acid (EPA). Intracellular ceramide accumulation was quantified using LC-ESI-MS/MS. PA but not LA upregulated IL-6 and TNFα. L-cycloserine, OA and EPA all counteracted PA-induced intracellular ceramide accumulation leading to a downregulation of IL-6 and TNFα. However, a TLR4 inhibitor failed to inhibit PA-induced upregulation of pro-inflammatory cytokines. In conclusion, PA induced the expression of IL-6 and TNFα in N42 neuronal cells independently of TLR4 but, partially, via ceramide synthesis with OA and EPA being anti-inflammatory by decreasing PA-induced intracellular ceramide build-up. Thus, ceramide accumulation represents one on the mechanisms by which PA induces inflammation in neurons.
Article
Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni−/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.
Article
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid (SFA), and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS, and treated with or without ASMase inhibitor amitriptyline. Neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of S1P production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- Mice and indicated that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
Article
As a potential drug for treating inflammatory, autoimmune diseases and cancers, the clinical use of triptolide (TP) is greatly limited due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.
Thesis
Les prévalences de l’obésité et du diabète de type 2 augmentent parallèlement. Ces deux pathologies sont liées à la sédentarité et à une alimentation riche en lipides. Lorsque la capacité de stockage du tissu adipeux est dépassée, les acides gras saturés en excès s’accumulent au niveau des tissus périphériques, comme les muscles squelettiques. Ces dépôts ectopiques de lipidiques conduisent à la formation de céramides (Cer) dans les cellules musculaires. Les Cer sont connus pour inhiber la signalisation insulinique en ciblant deux protéines majeures de cette voie, Akt et IRS-1. Le rôle délétère des Cer a été mis en évidence grâce à des analogues des Cer à chaînes courtes (C2-Cer). Les céramides endogènes sont produits au niveau du réticulum endoplasmique (RE) puis sont transportés par le transporteur CERT pour être métabolisés en sphingomyéline (SM) au niveau du Golgi. Mon projet de thèse s’est articulé en deux partie : (i) comprendre le rôle du transporteur CERT dans l’installation de l’insulinorésistance musculaire et (ii) comprendre comment les C2-Cer permettent de mimer l’effet de céramides endogènes à chaînes longues. Premièrement, nous avons observé que l’expression de CERT était diminuée en conditions lipotoxiques et nous avons montré l’importance du transport des Cer du RE vers le Golgi pour le maintien d’une bonne sensibilité à l’insuline des cellules en inhibant ou en surexprimant CERT in vitro et in vivo. Dans la seconde étude, nous avons montré que les C2-Cer étaient métabolisés en Cer endogènes à chaînes plus longues via la voie de recyclage, et que ces Cer endogènes étaient responsable de la perte de sensibilité à l’insuline des cellules.
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Background: Sphingolipids mainly consist of ceramides (Cer), sphingomyelins (SM) and glycosphingolipids. Sphingolipids are related with coronary heart disease and metabolic disease, but there're few studies about cerebrovascular disease. The purpose was to detect sphingolipids in plasma of patients with large artery atherosclerosis (LAA) cerebrovascular disease and cerebral small vessel disease (CSVD) to explore the similarities and differences of pathogenesis of the two subtypes. Methods: 20 patients with LAA cerebrovascular disease, 20 patients with age-related CSVD, 10 patients with Fabry disease and 14 controls were enrolled from October 2017 to January 2019. Ultra-high performance liquid chromatography-quadruple-time-of-flight mass spectrometry/mass spectrometry was used to determine sphingolipids. Univariate combined with multivariate analysis was used for comparison. Receiver operating characteristic curves were used to determine sensitivities and specificities. Results: 276 sphingolipids were detected, including 39 Cer, 3 ceramide phosphates, 72 glycosphingolipids and 162 SM. (1) Cer (d36:3), Cer (d34:2), Cer (d38:6), Cer (d36:4) and Cer (d16:0/18:1) were increased in LAA; SM (d34:1), Cer (d34:2), Cer (d36:4), Cer (d16:0/18:1), Cer (d38:6), Cer (d36:3) and Cer (d32:0) were increased in age-related CSVD. (2) Cer (d36:4) and SM (d34:1) were increased in age-related CSVD compared with LAA. (3) Total trihexosyl ceramides were increased in Fabry group compared with control (P<0.05); SM (d34:1) was increased in Fabry group. Conclusions: Ceramides are increased in both LAA and age-related CSVD, which may be related to similar risk factors and pathophysiological process of arteriosclerosis; SM is increased in both age-related CSVD and Fabry disease, suggesting that increased SM may be associated with CSVD. Glycosphingolipids, trihexosylceramides in particular, are increased in Fabry disease.
Article
Background and objectives: The relationship between metabolic stress, inflammation, and cardiovascular disease is being studied steadily. The aim of this study was to evaluate the effect of palmitate (PA) and minimally modified low-density lipoprotein (mmLDL) on macrophages and to identify the associated pathways. Methods: J774 macrophages were incubated with PA or mmLDL and lipopolysaccharide (LPS). Secretion of inflammatory chemokines and the expression of corresponding genes were determined. The phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase was also assessed. RNA sequencing of macrophages was performed to identify the genes regulated by PA or mmLDL. Some of the genes regulated by the 2 agents were validated by knocking down the cells using small interfering RNA. Results: PA or mmLDL promoted the secretion of interleukin (IL)-6 and IL-1β in LPS-stimulated macrophages, and this was accompanied by higher phosphorylation of ERK. RNA sequencing revealed dozens of genes that were regulated in this process, such as Csf3 and Edn1, which were affected by PA and mmLDL, respectively. These agents also increased Nlrp3 expression. The effect of Csf3 or Edn1 silencing on inflammation was modest, whereas toll-like receptor (TLR) 4 inhibition reduced a large proportion of macrophage activation. Conclusions: We demonstrated that the proinflammatory milieu with high levels of PA or mmLDL promoted macrophage activation and the expression of associated genes such as Nlrp3, Csf3, and Edn1. Although the TLR4 pathway appeared to be most relevant, additional role of other genes in this process provided insights regarding the potential targets for intervention.
Article
1. When geese or ducks are overfed with a high-energy diet rich in carbohydrates, their liver increases in size by 5- to 10-fold in 2 weeks, which is accompanied by the occurrence of hepatic steatosis. As a result, this distinctive genetic characteristic of waterfowl has been taken advantage of to produce foie gras. 2. When overfed geese were fed a regular diet for a 20-d period of recovery, their liver was restored to the original state. Hence, the entire process is reversible, and cause no lasting cirrhosis or necrosis in the liver. This suggests that waterfowl have a mechanism to protect their liver from the harm caused by severe hepatic steatosis. 3. This paper reviews the formation, physiological changes to metabolic pathways and the protective mechanisms in geese and ducks with hepatic steatosis. Not only will understanding these mechanisms provide ideas for the waterfowl breeding selection for foie gras, it is conducive to improving production efficiency and quality of foie gras. This provides a scientific basis to ensure animal welfare and an approach to the prevention and treatment of fatty liver disease in human.
Article
GPR40 is highly expressed in pancreatic islets and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice high-fat diet (HFD) for 20 weeks and then assessed the effect of GPR40-deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT), and GPR40-deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40-deficiency was associated with increased bodyweight, insulin, insulin resistance, cholesterol and ALT in control mice fed low fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40-deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40-deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40-deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.
Article
Beef tallow (BT) has attracted research interests of fish oil (FO) sparing in aquafeed, but total replacement of dietary FO by BT might damage aquatic animal health as a controversial issue for years. This study aimed to investigate the effects of BT partially or completely replacing FO on the health of red swamp crayfish (Procambarus clarkii), especially antioxidant capacity and immune response. Three experimental diets containing FO, BT and a blend of FO and BT (FB, 1:1) as lipid sources, respectively, were formulated to feed crayfish for 8 weeks. The results showed crayfish exhibited no significant differences (p > 0.05) in growth and body proximate composition regardless of dietary lipids. Crayfish fed a BT diet were observed higher contents of haemolymph triglyceride and free fatty acid (FFA) compared with crayfish fed FO (p < 0.05), while FB diet tended to reverse this effect. For hepatopancreas antioxidants, crayfish in the FB group showed higher levels of catalase and glutathione and lower malondialdehyde content than those in the FO group (p < 0.05). Furthermore, BT diet feeding decreased the contents of haemolymph acid phosphatase, lysozyme and total protein compared with FO diet, but FB diet tended to improve these immunological parameters. FB inclusion reversed the BT‐induced suppression of nuclear factor kappa beta mRNA expression and enhancement of mitochondrial manganese mRNA expression versus BT, implying ameliorative immunity function. Taken together, total replacement of dietary FO by BT might be detrimental to the health of crayfish, while partial substitution of dietary FO with BT neither suppresses growth nor impairs antioxidant capacity and innate immunity of crayfish.
Article
Fatty acid transport protein 4 (FATP4) belongs to a family of acyl-CoA synthetases which activate long-chain fatty acids into acyl-CoAs subsequently used in specific metabolic pathways. Patients with FATP4 mutations and Fatp4-null mice show thick desquamating skin and other complications, however, FATP4 role on macrophage functions has not been studied. We here determined whether the levels of macrophage glycerophospholipids, sphingolipids including ceramides, triacylglycerides, and cytokine release could be altered by FATP4 inactivation. Two in vitro experimental systems were studied: FATP4-knockdown in THP-1-derived macrophages undergoing M1 (LPS+IFNγ) or M2 (IL-4) activation and bone marrow-derived macrophages (BMDMs) from macrophage-specific Fatp4-knockout (Fatp4M-/-) mice undergoing tunicamycin (TM)-induced ER stress. FATP4-deficient macrophages showed a metabolic shift towards triacylglycerides and were protected from M1- or TM-induced release of pro-inflammatory cytokines and cellular injury. Fatp4M-/- BMDMs showed specificity in attenuating TM-induced activation of inositol-requiring enzyme1α, but not other unfolded protein response pathways. Under basal conditions, FATP4/Fatp4 deficiency decreased the levels of ceramides and induced an upregulation of mannose receptor CD206 expression. The deficiency led to an attenuation of IL-8 release in THP-1 cells as well as TNF-α and IL-12 release in BMDMs. Thus, FATP4 functions as an acyl-CoA synthetase in macrophages and its inactivation suppresses the release of pro-inflammatory cytokines by shifting fatty acids towards the synthesis of specific lipids.
Article
Severe equine asthma is characterized by airway hyperresponsiveness, neutrophilic inflammation and structural alterations of the lower airways. In asthmatic horses with neutrophilic inflammation, there is insensitivity to corticosteroids characterized by the persistence of neutrophils within the airways with therapy. We hypothesized that hypoxia or oxidative stress in the microenvironment of the lung contributes to this insensitivity of neutrophils to corticosteroids in asthmatic horses. Blood neutrophils isolated from horses with severe asthma (N = 8) and from healthy controls (N = 8) were incubated under different cell culture conditions simulating hypoxia and oxidative stress and, in the presence, or absence of dexamethasone. The pro-inflammatory gene and protein expression of neutrophils were studied. In both groups, pyocyanin-induced oxidative stress increased the mRNA expression of IL-8, IL-1β, and TNF-α. While IL-1β and TNF-α were downregulated by dexamethasone under these conditions, IL-8 was not. Simulated hypoxic conditions did not enhance pro-inflammatory gene expression in neutrophils from either group of horses. In conclusion, oxidative stress but not hypoxia may contribute to corticosteroid insensitivity via a selective gene regulation pathway. Equine neutrophil responses were similar in both heathy and asthmatic horses, indicating that it is not specific to asthmatic inflammation.
Article
Background Peripheral neuropathy is among the most common complications of diabetes, but a phenotypically identical distal sensory predominant, painful axonopathy afflicts patients with prediabetic metabolic syndrome, exemplifying a spectrum of risk and continuity of pathogenesis. No pharmacological treatment convincingly improves neuropathy in the setting of metabolic syndrome, but evolving data suggests that exercise may be a promising alternative. Objective To review in depth current literature regarding exercise treatment of metabolic syndrome neuropathy in humans and animal models, highlight the diverse mechanisms by which exercise exerts beneficial effects, and examine adherence limitations, safety aspects, modes and dose of exercise. Results Rodent models that recapitulate the organismal milieu of prediabetic metabolic syndrome and the phenotype of its neuropathy provide a strong platform to dissect exercise effects on neuropathy pathogenesis. In these models, exercise reverses hyperglycemia and consequent oxidative and nitrosative stress, improves microvascular vasoreactivity, enhances axonal transport, ameliorates the lipotoxicity and inflammatory effects of hyperlipidemia and obesity, supports neuronal survival and regeneration following injury, and enhances mitochondrial bioenergetics at the distal axon. Prospective human studies are limited in scale, but suggest exercise improves cutaneous nerve regenerative capacity, neuropathic pain, and task-specific functional performance measures of gait and balance. Like other heath behavioral interventions, benefits of exercise are limited by patient adherence. Conclusion Exercise is integrative therapy that potently reduces cellular inflammatory state and improves distal axonal oxidative metabolism to ameliorate features of neuropathy in metabolic syndrome. Intensity of exercise need not improve cardinal features of metabolic syndrome [e.g. weight, glucose control] to exert beneficial effects.
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Endotoxin in dairy products may pose risks to consumers’ health, but the effects of raw-milk total bacterial count (TBC) and thermal treatment temperature on endotoxin content of dairy products are not clear. In this study, TBC of raw milk and processed milk with different thermal treatment temperatures were detected by pilot processing experiment. We then verified it by detecting the endotoxin content of commercial dairy products. TBC was determined by conventional culture method, and the changes in alkaline phosphatase (ALP) and lactoperoxidase (LPO) activities in bovine milk before and after heat treatment were determined. The levels of fatty acids in bovine milk were detected by gas chromatography using a flame ionization detector (GC-FID). In the pilot experiment, raw milk was treated at 72, 75, 80, 85, 90, 95, 100, 105, 110, 115, and 120 ℃ for 15 s. After that, the raw milk was stored at 20 ℃ for 24 hours and 48 hours to greatly increase the TBC, and treated at 75 ℃ for 15 s and 90 ℃ for 15 s. The results show that the endotoxin content of sterilized milk increased with the increase in TBC and thermal treatment temperature. With the increase in thermal treatment temperature, the activities of ALP and LPO with endotoxin inhibition decreased. In addition, a total of 226 dairy samples were tested. The endotoxin content of 37 commercial PM milk samples were 6 EU/ml to 231 EU/ml, with 31 EU/ml to 1437 EU/ml for 40 commercial UHT milk samples, and 6 EU/ml to 9080 EU/ml for 149 reconstituted IFM samples. There was a significant difference in the endotoxin content of different dairy products (P < 0.05), and there was no significant difference between domestic and imported IFM (P > 0.05). This study found that TBC and thermal treatment temperature of raw milk could affect the endotoxin content of dairy products.
Article
Systemic inflammation is associated with an increased risk of non-communicable diseases, such as cardiovascular diseases and diabetes. Circulating fatty acids (FA) are known to be related to these conditions, possibly through their role in inflammation, although different types of FAs can have opposite effects on inflammatory mediators. The aim of the present study was to analyze the association of plasma FAs with inflammatory biomarkers in a PREDIMED trial subsample after one year of intervention. In a one-year longitudinal study of 91 participants of the PREDIMED trial (Barcelona-Clinic center), plasma FAs and inflammatory biomarkers were analyzed using gas chromatography and ELISA, respectively. In baseline plasma, a multivariable-adjusted ordinary least squares regression model showed that n-3 polyunsaturated FAs concentrations were inversely associated with concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin, whereas the level of the most abundant saturated FA, palmitic acid, was directly associated with concentrations of interleukin-6 (IL-6) (β = 0.48 pg/mL, 95% CI: 0.03, 0.93 per 1-SD increase, p-value = 0.037). After one year of nutritional intervention, changes of plasma diet-derived total saturated FAs and palmitic acid were directly associated with changes in IL-6 (β = 0.59 pg/mL [95% CI: 0.28, 0.89] per 1-SD, p-value = 0.001; β = 0.64 pg/mL, 95% CI: 0.31, 0.98, p-value = 0.001), respectively, after correction for multiple testing. Our findings suggest that saturated FAs of dietary origin, especially palmitic acid, are directly involved in the increase of IL-6 in plasma.
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Resumen La psoriasis es una enfermedad que va más allá de la afectación exclusivamente cutánea, cada día se reconoce más la importancia del compromiso sistémico, en especial por las comorbilidades asociadas. Dichas comorbilidades se explican por la marcada respuesta inflamatoria sistémica crónica mediada por citoquinas proinflamatorias (principalmente TNF-α, IL-23 e IL-17), las cuales desempeñan un papel importante en la inducción de la resistencia a la insulina, la disfunción endotelial, la aterosclerosis acelerada y el aumento del riesgo de eventos cardio-cerebrovasculares. La relación con estos desenlaces ha sido demostrada, y es allí donde surge el concepto de marcha psoriásica, un término que cobra cada día más importancia, cuyo objetivo es mantener y reforzar el enfoque de una enfermedad cutánea con compromiso sistémico, morbimortalidad asociada que puede ser prevenible y manejable. Los mecanismos fisiopatológicos que explican estos fenómenos son variables, sin embargo, se han dilucidado nuevos conceptos que han permitido mejorar el enfoque actual de la enfermedad, y así establecer mecanismos para disminuir el riesgo cardiovascular en pacientes con psoriasis.
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The objective of this study was to investigate whether serum high-sensitivity C-reactive protein (hs-CRP) concentration varies with dietary fatty acid intake in Iranian adults free of any history of cardiovascular disease (CVD). This cross-sectional study involved 8105 adults (3142 men) aged 35-65 years. Dietary intake was assessed using 24-h dietary recalls. The relationship between anthropometric, cardiometabolic risk factors and dietary data and serum hs-CRP was assessed using SPSS software. Median crude dietary saturated fat decreased across hs-CRP quarters (P =0.009 for linear trend), whereas energy-adjusted total fat (P =0.017), trans-fat (P =0.016), monounsaturated fatty acids (P =0.030) and cholesterol (P =0.005) monotonically increased, with some evidence of statistical interactions by gender. In conclusion, serum hs-CRP concentrations were associated with some components of dietary fatty acid intake in our population of individuals without CVD, suggesting that dietary fat intake could be associated with subclinical inflammation.
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Unlabelled: Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, CONTROL: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha, Control: 1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes ( Control: 2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.
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Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.
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Human keratinocytes (KC), when cultured under conditions to remain undifferentiated or to terminally differentiate, changed their cellular distribution of CD1d. As studied by confocal microscopy, undifferentiated KC had a pool of cytoplasmic CD1d, whereas after terminal differentiation, this molecule localized in the cell membrane, which recapitulates CD1d expression in vivo. A comparison of undifferentiated and differentiated cultured KC did not reveal any differences in the association with beta(2)-microglobulin, invariant chain of class II MHC, or patterns of glycosylation, suggesting that these biochemical properties are not regulating the cellular distribution of CD1d. Time-course studies of CD1d gene expression indicated that KC slowly increased gene expression with CaCl(2)-induced terminal differentiation. Increased CD1d gene expression was dependent on ceramide synthesis, because fumonisin B1, a ceramide synthetase inhibitor, blocked the increase in CD1d gene expression during terminal differentiation. Similarly, exogenous ceramide or the ceramidase inhibitor, B13, induced CD1d gene expression by undifferentiated, but not terminally differentiated, KC. A protein kinase C-zeta (PKC-zeta) inhibitor (a pseudosubstrate oligopeptide), but not a PKC-alphabeta inhibitor, significantly decreased CD1d gene expression by undifferentiated or ceramide-stimulated cultured, undifferentiated KC. As expected, downstream signaling events of PKC-zeta (JNK phosphorylation and NF-kappaBeta accumulation in the nucleus) were also attenuated. The calcineurin phosphatase inhibitor cyclosporine A, which blocks KC terminal differentiation, also blocked CD1d gene expression by cultured KC. In conclusion, this novel function of cellular ceramides extends the importance of this class of biologically active lipids beyond that of terminal differentiation and barrier function in normal human skin.
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TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
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Toll-like receptor 4 (TLR4) and TLR2 agonists from bacterial origin require acylated saturated fatty acids in their molecules. Previously, we reported that TLR4 activation is reciprocally modulated by saturated and polyunsaturated fatty acids in macrophages. However, it is not known whether fatty acids can modulate the activation of TLR2 or other TLRs for which respective ligands do not require acylated fatty acids. A saturated fatty acid, lauric acid, induced NFkappaB activation when TLR2 was co-transfected with TLR1 or TLR6 in 293T cells, but not when TLR1, 2, 3, 5, 6, or 9 was transfected individually. An n-3 polyunsaturated fatty acid (docosahexaenoic acid (DHA)) suppressed NFkappaB activation and cyclooxygenase-2 expression induced by the agonist for TLR2, 3, 4, 5, or 9 in a macrophage cell line (RAW264.7). Because dimerization is considered one of the potential mechanisms for the activation of TLR2 and TLR4, we determined whether the fatty acids modulate the dimerization. However, neither lauric acid nor DHA affected the heterodimerization of TLR2 with TLR6 as well as the homodimerization of TLR4 as determined by co-immunoprecipitation assays in 293T cells in which these TLRs were transiently overexpressed. Together, these results demonstrate that lauric acid activates TLR2 dimers as well as TLR4 for which respective bacterial agonists require acylated fatty acids, whereas DHA inhibits the activation of all TLRs tested. Thus, responsiveness of different cell types and tissues to saturated fatty acids would depend on the expression of TLR4 or TLR2 with either TLR1 or TLR6. These results also suggest that inflammatory responses induced by the activation of TLRs can be differentially modulated by types of dietary fatty acids.
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Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect. We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat-fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14(-)(/)(-) mutant mice mimicked the metabolic and inflammatory effects of antibiotics. This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.
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Background: The results of some epidemiologic studies conducted by using questionnaires suggest that dietary fat composition influences diabetes risk. Confirmation of this finding with use of a biomarker is warranted. Objective: We prospectively investigated the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid composition with the incidence of diabetes mellitus. Design: In 2909 adults aged 45–64 y, plasma fatty acid composition was quantified by using gas-liquid chromatography and was expressed as a percentage of total fatty acids. Incident diabetes (n = 252) was identified during 9 y of follow-up. Results: After adjustment for age, sex, baseline body mass index, waist-to-hip ratio, alcohol intake, cigarette smoking, physical activity, education, and parental history of diabetes, diabetes incidence was significantly and positively associated with the proportions of total saturated fatty acids in plasma CE and PL. The rate ratios of incident diabetes across quintiles of saturated fatty acids were 1.00, 1.36, 1.16, 1.60, and 2.08 (P = 0.0013) in CE and 1.00, 1.75, 1.87, 2.40, and 3.37 (P < 0.0001) in PL. In CE, the incidence of diabetes was also positively associated with the proportions of palmitic (16:0), palmitoleic (16:1n−7), and dihomo-γ-linolenic (20:3n−6) acids and inversely associated with the proportion of linoleic acid (18:2n−6). In PL, incident diabetes was positively associated with the proportions of 16:0 and stearic acid (18:0). Conclusions: The proportional saturated fatty acid composition of plasma is positively associated with the development of diabetes. Our findings with the use of this biomarker suggest indirectly that the dietary fat profile, particularly that of saturated fat, may contribute to the etiology of diabetes.
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