Stearic Acid Accumulation in Macrophages Induces Toll-Like Receptor 4/2-Independent Inflammation Leading to Endoplasmic Reticulum Stress–Mediated Apoptosis

Anderson, Emily K.; Hill, Andrea A.; Hasty, Alyssa H.

doi:10.1161/atvbaha.112.250142

Cited by 102 publications

(81 citation statements)

References 41 publications

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“…37,38 However, more recent reports have provided contrary evidence. 30,39 The present study is consistent with the concept that VLDL-stimulated macrophage inflammatory cytokine expression results from macrophage insulin resistance, rather than elicitation of a toll-like receptor-NFκB response. This is evidenced by the following: (1) impaired AKT/FoxO1 signaling and enhanced MAPK signaling by VLDL treatment, (2) canonical NF-κB target genes TNFα and IL-6 being unaffected by VLDL treatment, and (3) + It is tempting to hypothesize that VLDL-induced inflammatory responses are initially derived from rapid ERK1/2 activation followed by later and sustained AKT signaling.…”

Section: Discussionsupporting

confidence: 90%

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Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Bojic

Sawyez

Telford

et al. 2012

ATVB

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Objective-Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression. Methods and Results-THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced β-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1β, macrophage inflammatory protein 1α, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogenactivated protein kinase (MAPK) erk and AKT/forkhead box protein O1 signaling. Conclusion-The

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Section: Discussionsupporting

confidence: 90%

“…9,30 Paradoxically, FAs also activate PPARδ. 18 To reconcile this, macrophages were treated with oleic acid, which resulted in a marked induction of TG mass and expression of IL-1β and MIP-1α ( Figure VIA and VIB in the online-only Data Supplement).…”

Section: Inhibition Of Vldl-induced Inflammation By Pparδ Activation mentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Bojic

Sawyez

Telford

et al. 2012

ATVB

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“…Incubation of adipocytes and macrophages with saturated FAs enhances infl ammatory cytokine secretion, thereby linking saturated FAs to the infl ammatory process ( 42,43 ). Furthermore, diets rich in saturated fat, including the HFHC diet in the present study, induce macrophage infi ltration into adipose tissue and stimulate the infl ammatory response (44)(45)(46).…”

Section: Naringenin Prevents Lipid Accumulation and Infl Ammation In mentioning

confidence: 58%

Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr mice

Assini

Mulvihill

Sutherland

et al. 2013

Journal of Lipid Research

124

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Metabolic syndrome is a collection of abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance, all of which contribute to the development of type 2 diabetes and atherosclerosis. Insulin resistance, dyslipidemia, and atherosclerosis are amplifi ed by the development of a chronic low-grade infl ammatory response ( 1 ). In insulin-resistant states, monocyte-derived macrophages infi ltrate visceral adipose tissue, resulting in proinfl ammatory cytokine synthesis, either from adipocytes or resident macrophages, which impairs insulin sensitivity ( 2, 3 ). Administration of diets rich in saturated fats to Ldlr Ϫ / Ϫ mice represents a model with many characteristics of the metabolic syndrome ( 4-6 ). Recent studies in this Abstract Obesity-associated chronic infl ammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates infl ammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus fl avonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplifi ed infl ammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr ؊ / ؊ mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infi ltration and infl ammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and infl ammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of infl ammatory markers in peritoneal macrophages. Naringenin signifi cantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic infl ammation. We demonstrate that in mice fed cholesterolenriched diets, naringenin attenuates peripheral and systemic infl ammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation. -Assini, J. M., E. E. Mulvihill, B. G. Sutherland, D. E. Telford, C. G. Sawyez, S. L. Felder, S. Chhoker, J. Y. Edwards, R. Gros, and M. W. Huff. Naringenin prevents cholesterol-induced systemic infl ammation, This work was supported by Heart and Stroke Foundation of Ontario (HSFO)Grants , Canadian Foundation for Innovation and Ontario Research Fund (to R.G.), a HSFO Masters Award (to J.M.A.), and a Canadian Institutes of Health Research-Canada Graduate Scholarship Doctoral Award (to E.E.M.). 14 December 2012. Published, JLR Papers in Press, December 19, 2012 DOI 10.1194 Abbreviations: ABCG, ATP-binding...

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“…However, evidence from a number of experimental systems is emerging, stating that SFAs and UFAs have distinct contributions to lipotoxicity (25,26). SFAs such as palmitic acid (16:0) and stearic acid (18:0) induce apoptosis, oxidative stress, and ER stress in a variety of mammalian cell lines (including hepatocytes, macrophages, and VSMCs), whereas UFAs such as oleic acid have no or minimal lipotoxic properties (5,(25)(26)(27)(28)(29)(30). In addition, cotreatment with UFAs blocks SFA-mediated lipotoxic effects (25,29).…”

Section: Introductionmentioning

confidence: 99%

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

Masuda¹,

Miyazaki–Anzai²,

Keenan³

et al. 2015

Journal of Clinical Investigation

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R e s e a R c h a R t i c l e 4 5 4 4jci.org Volume 125 Number 12 December 2015 IntroductionVascular calcification is a major complication in patients who are aging, have diabetes, or have chronic kidney disease (CKD) and is an active process that differentiates vascular smooth muscle cells (VSMCs) into osteoblast-like cells (1, 2). This process is highly regulated by transcription factors involved in osteogenic differentiation, such as RUNX2, MSX2, and ATF4 (3-5). Several in vitro and in vivo studies have shown lipids to play a causative role in the pathogenesis of vascular calcification in addition to inorganic phosphate, inflammatory cytokines, and oxidative stress (6-13). Treatment with unsaturated fatty acids (UFAs) inhibits vascular mineralization and osteogenic differentiation (14, 15), whereas oxidized lipids, such as oxysterols and oxidized phospholipids, elicit procalcific effects in vascular cells (9,16,17). In addition to this evidence, we also previously reported that saturated fatty acids (SFAs) and calcium simultaneously accumulate during osteogenic differentiation of vascular cells (18,19). Ectopic accumulation of excess lipids, called lipotoxicity, plays a central role in the pathogenesis of cardio-metabolic diseases, including diabetes, obesity, atherosclerosis, and vascular calcification (20-24). However, evidence from a number of experimental systems is emerging, stating that SFAs and UFAs have distinct contributions to lipotoxicity (25,26). SFAs such as palmitic acid (16:0) and stearic acid (18:0) induce apoptosis, oxidative stress, and ER stress in a variety of mammalian cell lines (including hepatocytes, macrophages, and VSMCs), whereas UFAs such as oleic acid have no or minimal lipotoxic properties (5,(25)(26)(27)(28)(29)(30). In addition, cotreatment with UFAs blocks SFA-mediated lipotoxic effects (25,29). However, the specific metabolite of SFAs that induces lipotoxicity, the mechanism underlying SFA-mediated lipotoxicity, and how UFAs block SFA-mediated lipotoxicity are largely unknown.Proper intracellular SFA and UFA balance is controlled by a lipogenic enzyme called stearoyl-CoA desaturase (SCD) (31,32). SCD catalyzes the conversion of SFAs to monounsaturated FAs, mainly 16:0 into palmitoleate (16:1n-7), and 18:0 into oleate (18:1n-9) (33,34). This introduction of a double bond markedly impacts several chemical properties, including a decrease in melting point and an increase in solubility. The activation of SCD therefore neutralizes SFA-mediated lipotoxicity (5, 25). The expression of SCD is highly regulated by a number of hormonal and dietary factors (33,(35)(36)(37). Recently, we found that the accumulation of SFAs by either supplementation with exogenous SFAs or inhibition of SCD induces mineralization of VSMCs (5,19). In addition, SFA-mediated lipotoxicity and vascular calcification were completely blocked by an acyl-CoA synthetase inhibitor and were attenuated by the shRNA-mediated inhibition of fatty acid elongase-6 (Elovl6) (5), suggesting that stearoyl-CoA (18:0-CoA) or its ...

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Stearic Acid Accumulation in Macrophages Induces Toll-Like Receptor 4/2-Independent Inflammation Leading to Endoplasmic Reticulum Stress–Mediated Apoptosis

Cited by 102 publications

References 41 publications

Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein

Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr mice

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

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