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Targeting inflammation in metabolic syndrome

      The metabolic syndrome (MetS) is comprised of a cluster of closely related risk factors, including visceral adiposity, insulin resistance, hypertension, high triglyceride, and low high-density lipoprotein cholesterol; all of which increase the risk for the development of type 2 diabetes and cardiovascular disease. A chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance and MetS. In this review, we summarize recent research which has provided insight into the mechanisms by which inflammation underlies the pathophysiology of the individual components of MetS including visceral adiposity, hyperglycemia and insulin resistance, dyslipidemia, and hypertension. On the basis of these mechanisms, we summarize therapeutic modalities to target inflammation in the MetS and its individual components. Current therapeutic modalities can modulate the individual components of MetS and have a direct anti-inflammatory effect. Lifestyle modifications including exercise, weight loss, and diets high in fruits, vegetables, fiber, whole grains, and low-fat dairy and low in saturated fat and glucose are recommended as a first line therapy. The Mediterranean and dietary approaches to stop hypertension diets are especially beneficial and have been shown to prevent development of MetS. Moreover, the Mediterranean diet has been associated with reductions in total and cardiovascular mortality. Omega-3 fatty acids and peroxisome proliferator–activated receptor α agonists lower high levels of triglyceride; their role in targeting inflammation is reviewed. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers comprise pharmacologic therapies for hypertension but also target other aspects of MetS including inflammation. Statin drugs target many of the underlying inflammatory pathways involved in MetS.

      Abbreviations:

      AA (arachidonic acid), ABCA1 (adenosine triphosphate-binding cassette transporter A1), ACE-I (angiotensin-converting enzyme inhibitor), ACSL1 (acyl-CoA synthase 1), ADMA (asymmetric dimethylarginine), Akt (protein kinase B), Aldo (aldosterone), AMPK (adenosine monophosphate-activated protein kinase), ANGPTL (angiopoietin-like protein), Ang (angiotensin), AngII (angiotensin II), AP-1 (activator protein 1), Apo (apolipoprotein), ARB (angiotensin receptor blocker), Aspirin-COX-2 (aspirin-acetylated cyclooxygenase-2), AT-LX (aspirin-triggered lipoxins), AT-PD1 (aspirin-triggered protectins), AT-RvD (aspirin-triggered resolvins), C (cholesterol), CAD (coronary artery disease), CD (cluster of differentiation), CE (cholesterol ester), CETP (CE transfer protein), CoQ10 (coenzyme Q10), COX (cyclooxygenase), COX-2 (cyclooxygenase-2), CRP (C-reactive protein), c-Src (tyrosine-protein kinase C-Src Kinase), CVD (cardiovascular disease), DAG (diacylglycerides), DHA (docosahexaenoic acid), EF (ejection fraction), eNOS (endothelial nitric oxide synthase), EPA (eicosapentaenoic acid), ET (endothelin), FetA (Fetuin A), FFA (free fatty acids), FoxO1 (forkhead box protein O1), Glu (glucose), GLUT-4 (glucose transporter type 4), GPR (G-protein–coupled receptor), GRK2 (G-protein–coupled receptor kinase 2), HDL (high-density lipoprotein), HL (hepatic lipase), HR (hazard ratio), ICAM-1 (intercellular adhesion molecule-1), IDL (intermediate-density lipoprotein), IKK (inhibitor of nuclear factor kappa-B kinase), IL (interleukin), ILR (interleukin receptor), iNOS (inducible nitric oxide synthase), LT (leukotriene), IRS (insulin receptor substrate), IκB (inhibitor of nuclear factor kappa-B), JNK (c-Jun N-terminal kinase), LOX (lipoxygenase), LPL (lipoprotein lipase), LX (lipoxin), MAPK (Mitogen-activated protein kinases), MCP-1 (monocyte chemoattractant protein-1), MetS (metabolic syndrome), MI (myocardial infarction), MMP (matrix metalloproteinase), MTP (microsomal triglyceride transfer protein), NF-κB (nuclear factor kappa-B), NLR (nod-like receptor), NO (nitric oxide), Omega-3 FAs (omega-3 fatty acids), oxLDL (oxidized low-density lipoprotein), PAI-1 (plasminogen activator inhibitor-1), PD1 (protectins), PG (prostaglandins), PI3K (phosphatidylinositol 3-kinase), PKC (protein kinase C), PPAR (peroxisome proliferator–activated receptor), RAAS (renin–angiotensin–aldosterone system), RCT (reverse cholesterol transport), ROS (reactive oxygen species), RvD (DHA-derived resolvins), RvE (EPA-derived resolvins), S1P (sphingosine-1-phosphate), SAA (serum amyloid A), SFA (saturated fatty acids), SOCS-3 (suppressor of cytokine signaling 3), SPMs (specialized proresolving lipid mediators), TF (tissue factor), TG (triglycerides), Th (T-helper cells), TLR (toll-like receptor), TNF-α (tumor necrosis factor α), Treg (T-regulatory cell), TX (thromboxane), VCAM-1 (vascular cell adhesion molecule-1), VLDL (very low–density lipoprotein)
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      References

        • Wilson P.W.
        • Kannel W.B.
        • Silbershatz H.
        • D'Agostino R.B.
        Clustering of metabolic factors and coronary heart disease.
        Arch Intern Med. 1999; 159: 1104-1109
        • Alberti K.G.
        • Eckel R.H.
        • Grundy S.M.
        • et al.
        Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
        Circulation. 2009; 120: 1640-1645
        • Ford E.S.
        • Giles W.H.
        • Dietz W.H.
        Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.
        JAMA. 2002; 287: 356-359
        • Havel R.J.
        • Kane J.P.
        Introduction: structure and metabolism of plasma lipoproteins.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic and molecular bases of inherited disease. 7 ed. McGraw-Hill, New York1995: 1841-1851
        • Spite M.
        • Claria J.
        • Serhan C.N.
        Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.
        Cell Metab. 2014; 19: 21-36
        • Donath M.Y.
        • Shoelson S.E.
        Type 2 diabetes as an inflammatory disease.
        Nat Rev Immunol. 2011; 11: 98-107
        • Gao Z.
        • Hwang D.
        • Bataille F.
        • et al.
        Serine phosphorylation of insulin- receptor substrate 1 by inhibitor kappa B kinase complex.
        J Biol Chem. 2002; 277: 48115-48121
        • Zhang J.
        • Gao Z.
        • Yin J.
        • Quon M.J.
        • Ye J.
        S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2.
        J Biol Chem. 2008; 283: 35375-35382
        • Dandona P.
        • Aljada A.
        • Mohanty P.
        • et al.
        Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?.
        J Clin Endocrinol Metab. 2001; 86: 3257-3265
        • Wang S.
        • Leonard S.S.
        • Castranova V.
        • Vallyathan V.
        • Shi X.
        The role of superoxide radical in TNF-alpha induced NF-kappaB activation.
        Ann Clin Lab Sci. 1999; 29: 192-199
        • Diez J.J.
        • Iglesias P.
        The role of the novel adipocyte-derived hormone adiponectin in human disease.
        Eur J Endocrinol. 2003; 148: 293-300
        • Ukkola O.
        • Santaniemi M.
        Adiponectin: a link between excess adiposity and associated comorbidities?.
        J Mol Med (Berl). 2002; 80: 696-702
        • Stanya K.J.
        • Jacobi D.
        • Liu S.
        • et al.
        Direct control of hepatic glucose production by interleukin-13 in mice.
        J Clin Invest. 2013; 123: 261-271
        • Sugimoto R.
        • Enjoji M.
        • Nakamuta M.
        • et al.
        Effect of IL-4 and IL-13 on collagen production in cultured LI90 human hepatic stellate cells.
        Liver Int. 2005; 25: 420-428
        • Guilherme A.
        • Virbasius J.V.
        • Puri V.
        • Czech M.P.
        Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.
        Nat Rev Mol Cell Biol. 2008; 9: 367-377
        • Glass C.K.
        • Olefsky J.M.
        Inflammation and lipid signaling in the etiology of insulin resistance.
        Cell Metab. 2012; 15: 635-645
        • Nguyen M.T.
        • Favelyukis S.
        • Nguyen A.K.
        • et al.
        A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.
        J Biol Chem. 2007; 282: 35279-35292
        • Kawakami A.
        • Aikawa M.
        • Libby P.
        • Alcaide P.
        • Luscinskas F.W.
        • Sacks F.M.
        Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells.
        Circulation. 2006; 113: 691-700
        • Kawakami A.
        • Aikawa M.
        • Alcaide P.
        • Luscinskas F.W.
        • Libby P.
        • Sacks F.M.
        Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells.
        Circulation. 2006; 114: 681-687
        • Shi H.
        • Kokoeva M.V.
        • Inouye K.
        • Tzameli I.
        • Yin H.
        • Flier J.S.
        TLR4 links innate immunity and fatty acid-induced insulin resistance.
        J Clin Invest. 2006; 116: 3015-3025
        • Samuel V.T.
        • Shulman G.I.
        Mechanisms for insulin resistance: common threads and missing links.
        Cell. 2012; 148: 852-871
        • Stratford S.
        • Hoehn K.L.
        • Liu F.
        • Summers S.A.
        Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B.
        J Biol Chem. 2004; 279: 36608-36615
        • Wen H.
        • Gris D.
        • Lei Y.
        • et al.
        Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
        Nat Immunol. 2011; 12: 408-415
        • Wen H.
        • Ting J.P.
        • O'Neill L.A.
        A role for the NLRP3 inflammasome in metabolic diseases–did Warburg miss inflammation?.
        Nat Immunol. 2012; 13: 352-357
        • Usui I.
        • Imamura T.
        • Babendure J.L.
        • et al.
        G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes.
        Mol Endocrinol. 2005; 19: 2760-2768
        • Santulli G.
        • Trimarco B.
        • Iaccarino G.
        G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms.
        High Blood Press Cardiovasc Prev. 2013; 20: 5-12
        • Cipolletta E.
        • Campanile A.
        • Santulli G.
        • et al.
        The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance.
        Cardiovasc Res. 2009; 84: 407-415
        • Ciccarelli M.
        • Chuprun J.K.
        • Rengo G.
        • et al.
        G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.
        Circulation. 2011; 123: 1953-1962
        • Hadad N.
        • Burgazliev O.
        • Elgazar-Carmon V.
        • et al.
        Induction of cytosolic phospholipase a2alpha is required for adipose neutrophil infiltration and hepatic insulin resistance early in the course of high-fat feeding.
        Diabetes. 2013; 62: 3053-3063
        • Clark J.D.
        • Schievella A.R.
        • Nalefski E.A.
        • Lin L.L.
        Cytosolic phospholipase A2.
        J Lipid Mediat Cell Signal. 1995; 12: 83-117
        • Gallin J.I.
        • Snyderman R.
        • Fearon D.T.
        • Haynes B.F.
        • Nathan C.
        Inflammation: basic principles and clinical correlates.
        Lippincott Williams & Wilkins, Philadelphia, Philadelphia1999
        • Williams T.J.
        • Peck M.J.
        Role of prostaglandin-mediated vasodilatation in inflammation.
        Nature. 1977; 270: 530-532
        • Nathan C.
        Points of control in inflammation.
        Nature. 2002; 420: 846-852
        • Hellmann J.
        • Zhang M.J.
        • Tang Y.
        • Rane M.
        • Bhatnagar A.
        • Spite M.
        Increased saturated fatty acids in obesity alter resolution of inflammation in part by stimulating prostaglandin production.
        J Immunol. 2013; 191: 1383-1392
        • Kasama T.
        • Miwa Y.
        • Isozaki T.
        • Odai T.
        • Adachi M.
        • Kunkel S.L.
        Neutrophil-derived cytokines: potential therapeutic targets in inflammation.
        Curr Drug Targets Inflamm Allergy. 2005; 4: 273-279
        • Scher J.U.
        • Abramson S.B.
        • Pillinger M.H.
        Neutrophils I.
        in: Serhan C.N. Ward P.A. Gilroy D.W. Fundamentals of inflammation. Cambridge University Press, Cambridge2010
        • Horrillo R.
        • Gonzalez-Periz A.
        • Martinez-Clemente M.
        • et al.
        5-lipoxygenase activating protein signals adipose tissue inflammation and lipid dysfunction in experimental obesity.
        J Immunol. 2010; 184: 3978-3987
        • Bannenberg G.L.
        • Chiang N.
        • Ariel A.
        • et al.
        Molecular circuits of resolution: formation and actions of resolvins and protectins.
        J Immunol. 2005; 174: 4345-4355
        • Li S.
        • Sun Y.
        • Liang C.P.
        • et al.
        Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet.
        Circ Res. 2009; 105: 1072-1082
        • Takano T.
        • Clish C.B.
        • Gronert K.
        • Petasis N.
        • Serhan C.N.
        Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues.
        J Clin Invest. 1998; 101: 819-826
        • Serhan C.N.
        • Maddox J.F.
        • Petasis N.A.
        • et al.
        Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils.
        Biochemistry. 1995; 34: 14609-14615
        • Maddox J.F.
        • Serhan C.N.
        Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction.
        J Exp Med. 1996; 183: 137-146
        • Godson C.
        • Mitchell S.
        • Harvey K.
        • Petasis N.A.
        • Hogg N.
        • Brady H.R.
        Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages.
        J Immunol. 2000; 164: 1663-1667
        • Buckley C.D.
        • Gilroy D.W.
        • Serhan C.N.
        Proresolving lipid mediators and mechanisms in the resolution of acute inflammation.
        Immunity. 2014; 40: 315-327
        • Serhan C.N.
        • Clish C.B.
        • Brannon J.
        • Colgan S.P.
        • Chiang N.
        • Gronert K.
        Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.
        J Exp Med. 2000; 192: 1197-1204
        • Serhan C.N.
        • Hong S.
        • Gronert K.
        • et al.
        Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.
        J Exp Med. 2002; 196: 1025-1037
        • Hong S.
        • Gronert K.
        • Devchand P.R.
        • Moussignac R.L.
        • Serhan C.N.
        Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation.
        J Biol Chem. 2003; 278: 14677-14687
        • Levy B.D.
        • Clish C.B.
        • Schmidt B.
        • Gronert K.
        • Serhan C.N.
        Lipid mediator class switching during acute inflammation: signals in resolution.
        Nat Immunol. 2001; 2: 612-619
        • Gilroy D.W.
        • Colville-Nash P.R.
        • Willis D.
        • Chivers J.
        • Paul-Clark M.J.
        • Willoughby D.A.
        Inducible cyclooxygenase may have anti-inflammatory properties.
        Nat Med. 1999; 5: 698-701
        • Kanter J.E.
        • Kramer F.
        • Barnhart S.
        • et al.
        Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.
        Proc Natl Acad Sci U S A. 2012; 109: E715-E724
        • O'Brien B.A.
        • Geng X.
        • Orteu C.H.
        • et al.
        A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse.
        J Autoimmun. 2006; 26: 104-115
        • O'Brien B.A.
        • Huang Y.
        • Geng X.
        • Dutz J.P.
        • Finegood D.T.
        Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced.
        Diabetes. 2002; 51: 2481-2488
        • Gyurko R.
        • Siqueira C.C.
        • Caldon N.
        • Gao L.
        • Kantarci A.
        • Van Dyke T.E.
        Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice.
        J Immunol. 2006; 177: 7250-7256
        • Berriot-Varoqueaux N.
        • Aggerbeck L.P.
        • Samson-Bouma M.
        • Wetterau J.R.
        The role of the microsomal triglyceride transfer protein in abetalipoproteinemia.
        Annu Rev Nutr. 2000; 20: 663-697
        • Sehayek E.
        • Lewin-Velvert U.
        • Chajek-Shaul T.
        • Eisenberg S.
        Lipolysis exposes unreactive endogenous apolipoprotein E-3 in human and rat plasma very low density lipoprotein.
        J Clin Invest. 1991; 88: 553-560
        • Beigneux A.P.
        • Davies B.S.
        • Gin P.
        • et al.
        Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons.
        Cell Metab. 2007; 5: 279-291
        • Ooi E.M.
        • Barrett P.H.
        • Chan D.C.
        • Watts G.F.
        Apolipoprotein C-III: understanding an emerging cardiovascular risk factor.
        Clin Sci (Lond). 2008; 114: 611-624
        • Zheng C.
        • Khoo C.
        • Furtado J.
        • Sacks F.M.
        Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.
        Circulation. 2010; 121: 1722-1734
        • Rapp R.J.
        Hypertriglyceridemia: a review beyond low-density lipoprotein.
        Cardiology. 2002; 10: 163-172
        • Kawakami A.
        • Osaka M.
        • Aikawa M.
        • et al.
        Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation.
        Circ Res. 2008; 103: 1402-1409
        • Lee S.J.
        • Campos H.
        • Moye L.A.
        • Sacks F.M.
        LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients.
        Arterioscler Thromb Vasc Biol. 2003; 23: 853-858
        • Pollin T.I.
        • Damcott C.M.
        • Shen H.
        • et al.
        A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.
        Science. 2008; 322: 1702-1705
        • Petersen K.F.
        • Dufour S.
        • Hariri A.
        • et al.
        Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.
        N Engl J Med. 2010; 362: 1082-1089
        • Tsai M.Y.
        • Ordovas J.M.
        APOC3 mutation, serum triglyceride concentrations, and coronary heart disease.
        Clin Chem. 2009; 55: 1274-1276
        • Santulli G.
        Angiopoietin-like proteins: a comprehensive look.
        Front Endocrinol. 2014; 5: 4
        • Robciuc M.R.
        • Maranghi M.
        • Lahikainen A.
        • et al.
        Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids.
        Arterioscler Thromb Vasc Biol. 2013; 33: 1706-1713
        • Nakajima K.
        • Kobayashi J.
        Antibodies to human angiopoietin-like protein 3: a patent evaluation of WO2012174178.
        Expert Opin Ther Pat. 2014; 24: 113-119
        • Fabbrini E.
        • Mohammed B.S.
        • Magkos F.
        • Korenblat K.M.
        • Patterson B.W.
        • Klein S.
        Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.
        Gastroenterology. 2008; 134: 424-431
        • Sparks J.D.
        • Sparks C.E.
        Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes.
        J Biol Chem. 1990; 265: 8854-8862
        • Ginsberg H.N.
        • Fisher E.A.
        The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism.
        J Lipid Res. 2009; 50: S162-S166
        • Pavlic M.
        • Valero R.
        • Duez H.
        • et al.
        Triglyceride-rich lipoprotein-associated apolipoprotein C-III production is stimulated by plasma free fatty acids in humans.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1660-1665
        • Sato R.
        • Miyamoto W.
        • Inoue J.
        • Terada T.
        • Imanaka T.
        • Maeda M.
        Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription.
        J Biol Chem. 1999; 274: 24714-24720
        • Eckel R.H.
        The complex metabolic mechanisms relating obesity to hypertriglyceridemia.
        Arterioscler Thromb Vasc Biol. 2011; 31: 1946-1948
        • Yancey P.G.
        • Bortnick A.E.
        • Kellner-Weibel G.
        • de la Llera-Moya M.
        • Phillips M.C.
        • Rothblat G.H.
        Importance of different pathways of cellular cholesterol efflux.
        Arterioscler Thromb Vasc Biol. 2003; 23: 712-719
        • Steinberg D.
        A docking receptor for HDL cholesterol esters.
        Science. 1996; 271: 460-461
        • Lamarche B.
        • Uffelman K.D.
        • Carpentier A.
        • et al.
        Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.
        J Clin Invest. 1999; 103: 1191-1199
        • Swenson T.L.
        The role of the cholesteryl ester transfer protein in lipoprotein metabolism.
        Diabetes Metab Rev. 1991; 7: 139-153
        • Brinton E.A.
        • Eisenberg S.
        • Breslow J.L.
        Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution.
        Arterioscler Thromb. 1994; 14: 707-720
        • Han C.Y.
        • Chiba T.
        • Campbell J.S.
        • et al.
        Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes.
        Arterioscler Thromb Vasc Biol. 2006; 26: 1806-1813
        • Uhlar C.M.
        • Whitehead A.S.
        Serum amyloid A, the major vertebrate acute-phase reactant.
        Eur J Biochem. 1999; 265: 501-523
        • Undurti A.
        • Huang Y.
        • Lupica J.A.
        • Smith J.D.
        • DiDonato J.A.
        • Hazen S.L.
        Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle.
        J Biol Chem. 2009; 284: 30825-30835
        • Van Lenten B.J.
        • Navab M.
        • Shih D.
        • Fogelman A.M.
        • Lusis A.J.
        The role of high-density lipoproteins in oxidation and inflammation.
        Trends Cardiovasc Med. 2001; 11: 155-161
        • McGillicuddy F.C.
        • de la Llera Moya M.
        • Hinkle C.C.
        • et al.
        Inflammation impairs reverse cholesterol transport in vivo.
        Circulation. 2009; 119: 1135-1145
        • Van Lenten B.J.
        • Hama S.Y.
        • de Beer F.C.
        • et al.
        Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.
        J Clin Invest. 1995; 96: 2758-2767
        • Navab M.
        • Ananthramaiah G.M.
        • Reddy S.T.
        • et al.
        The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL.
        J Lipid Res. 2004; 45: 993-1007
        • Owen D.M.
        • Magenau A.
        • Williamson D.
        • Gaus K.
        The lipid raft hypothesis revisited–new insights on raft composition and function from super-resolution fluorescence microscopy.
        Bioessays. 2012; 34: 739-747
        • Haraba R.A.
        • Antohe F.
        T cells are active participants in the progression of atherosclerotic plaques.
        Dig J Nanomater Biostruct. 2011; 6
        • Taleb S.
        • Tedgui A.
        • Mallat Z.
        Adaptive T cell immune responses and atherogenesis.
        Curr Opin Pharmacol. 2010; 10: 197-202
        • Lichtman A.H.
        T cell costimulatory and coinhibitory pathways in vascular inflammatory diseases.
        Front Physiol. 2012; 3: 18
        • Lahoute C.
        • Herbin O.
        • Mallat Z.
        • Tedgui A.
        Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets.
        Nat Rev Cardiol. 2011; 8: 348-358
        • Foks A.C.
        • Frodermann V.
        • ter Borg M.
        • et al.
        Differential effects of regulatory T cells on the initiation and regression of atherosclerosis.
        Atherosclerosis. 2011; 218: 53-60
        • Ait-Oufella H.
        • Salomon B.L.
        • Potteaux S.
        • et al.
        Natural regulatory T cells control the development of atherosclerosis in mice.
        Nat Med. 2006; 12: 178-180
        • Maganto-Garcia E.
        • Tarrio M.L.
        • Grabie N.
        • Bu D.X.
        • Lichtman A.H.
        Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia.
        Circulation. 2011; 124: 185-195
        • Feuerer M.
        • Herrero L.
        • Cipolletta D.
        • et al.
        Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.
        Nat Med. 2009; 15: 930-939
        • Winer D.A.
        • Winer S.
        • Shen L.
        • et al.
        B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.
        Nat Med. 2011; 17: 610-617
        • McLaughlin T.
        • Liu L.F.
        • Lamendola C.
        • et al.
        T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans.
        Arterioscler Thromb Vasc Biol. 2014; 34: 2637-2643
        • Wilhelm A.J.
        • Zabalawi M.
        • Owen J.S.
        • et al.
        Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice.
        J Biol Chem. 2010; 285: 36158-36169
        • Wilhelm A.J.
        • Zabalawi M.
        • Grayson J.M.
        • et al.
        Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity.
        Arterioscler Thromb Vasc Biol. 2009; 29: 843-849
        • Dong L.
        • Watanabe K.
        • Itoh M.
        • et al.
        CD4+ T-cell dysfunctions through the impaired lipid rafts ameliorate concanavalin A-induced hepatitis in sphingomyelin synthase 1-knockout mice.
        Int Immunol. 2012; 24: 327-337
        • Yin K.
        • Chen W.J.
        • Zhou Z.G.
        • et al.
        Apolipoprotein A-I inhibits CD40 proinflammatory signaling via ATP-binding cassette transporter A1-mediated modulation of lipid raft in macrophages.
        J Atheroscler Thromb. 2012; 19: 823-836
        • Cheng A.M.
        • Handa P.
        • Tateya S.
        • et al.
        Apolipoprotein A-I attenuates palmitate-mediated NF-kappaB activation by reducing Toll-like receptor-4 recruitment into lipid rafts.
        PLoS One. 2012; 7: e33917
        • Sorci-Thomas M.G.
        • Thomas M.J.
        High density lipoprotein biogenesis, cholesterol efflux, and immune cell function.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2561-2565
        • Nofer J.R.
        • van der Giet M.
        • Tolle M.
        • et al.
        HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3.
        J Clin Invest. 2004; 113: 569-581
        • Gong M.
        • Wilson M.
        • Kelly T.
        • et al.
        HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner.
        J Clin Invest. 2003; 111: 1579-1587
        • Mineo C.
        • Shaul P.W.
        HDL stimulation of endothelial nitric oxide synthase: a novel mechanism of HDL action.
        Trends Cardiovasc Med. 2003; 13: 226-231
        • Drew B.G.
        • Fidge N.H.
        • Gallon-Beaumier G.
        • Kemp B.E.
        • Kingwell B.A.
        High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation.
        Proc Natl Acad Sci U S A. 2004; 101: 6999-7004
        • Ruan X.
        • Li Z.
        • Zhang Y.
        • et al.
        Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat.
        J Cell Mol Med. 2011; 15: 763-772
        • Drew B.G.
        • Duffy S.J.
        • Formosa M.F.
        • et al.
        High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.
        Circulation. 2009; 119: 2103-2111
        • Kemp B.E.
        • Mitchelhill K.I.
        • Stapleton D.
        • Michell B.J.
        • Chen Z.P.
        • Witters L.A.
        Dealing with energy demand: the AMP-activated protein kinase.
        Trends Biochem Sci. 1999; 24: 22-25
        • Zhou G.
        • Myers R.
        • Li Y.
        • et al.
        Role of AMP-activated protein kinase in mechanism of metformin action.
        J Clin Invest. 2001; 108: 1167-1174
        • Cochran B.J.
        • Bisoendial R.J.
        • Hou L.
        • et al.
        Apolipoprotein A-I increases insulin secretion and production from pancreatic beta-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism.
        Arterioscler Thromb Vasc Biol. 2014; 34: 2261-2267
        • Hao M.
        • Head W.S.
        • Gunawardana S.C.
        • Hasty A.H.
        • Piston D.W.
        Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.
        Diabetes. 2007; 56: 2328-2338
        • Ishikawa M.
        • Iwasaki Y.
        • Yatoh S.
        • et al.
        Cholesterol accumulation and diabetes in pancreatic beta-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity.
        J Lipid Res. 2008; 49: 2524-2534
        • Iwasaki Y.
        • Iwasaki H.
        • Yatoh S.
        • et al.
        Nuclear SREBP-1a causes loss of pancreatic beta-cells and impaired insulin secretion.
        Biochem Biophys Res Commun. 2009; 378: 545-550
        • Rutti S.
        • Ehses J.A.
        • Sibler R.A.
        • et al.
        Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells.
        Endocrinology. 2009; 150: 4521-4530
        • Vikman J.
        • Jimenez-Feltstrom J.
        • Nyman P.
        • Thelin J.
        • Eliasson L.
        Insulin secretion is highly sensitive to desorption of plasma membrane cholesterol.
        FASEB J. 2009; 23: 58-67
        • Koseki M.
        • Matsuyama A.
        • Nakatani K.
        • et al.
        Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations.
        J Atheroscler Thromb. 2009; 16: 292-296
        • Vergeer M.
        • Brunham L.R.
        • Koetsveld J.
        • et al.
        Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction.
        Diabetes Care. 2010; 33: 869-874
        • Connor T.
        • Martin S.D.
        • Howlett K.F.
        • McGee S.L.
        Metabolic remodelling in obesity and type 2 diabetes: pathological or protective mechanisms in response to nutrient excess?.
        Clin Exp Pharmacol Physiol. 2015; 42: 109-115
        • National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A
        Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
        Circulation. 2002; 106: 3143-3421
        • Knowler W.C.
        • Barrett-Connor E.
        • Fowler S.E.
        • et al.
        Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
        N Engl J Med. 2002; 346: 393-403
        • Hotamisligil G.S.
        • Shargill N.S.
        • Spiegelman B.M.
        Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
        Science. 1993; 259: 87-91
        • Mohanty P.
        • Hamouda W.
        • Garg R.
        • Aljada A.
        • Ghanim H.
        • Dandona P.
        Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes.
        J Clin Endocrinol Metab. 2000; 85: 2970-2973
        • Aljada A.
        • Ghanim H.
        • Mohanty P.
        • Syed T.
        • Bandyopadhyay A.
        • Dandona P.
        Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations.
        Am J Clin Nutr. 2004; 80: 51-57
        • Mohanty P.
        • Ghanim H.
        • Hamouda W.
        • Aljada A.
        • Garg R.
        • Dandona P.
        Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.
        Am J Clin Nutr. 2002; 75: 767-772
        • Aljada A.
        • Mohanty P.
        • Ghanim H.
        • et al.
        Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect.
        Am J Clin Nutr. 2004; 79: 682-690
        • Mohanty P.
        • Daoud N.
        • Ghanim H.
        • et al.
        Absence of oxidative stress and inflammation following the intake of a 900 kcalorie meal rich in fruit and fiber.
        Diabetes. 2004; 53: A405
        • Dandona P.
        • Mohanty P.
        • Ghanim H.
        • et al.
        The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation.
        J Clin Endocrinol Metab. 2001; 86: 355-362
        • Dandona P.
        • Mohanty P.
        • Hamouda W.
        • et al.
        Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations.
        J Clin Endocrinol Metab. 2001; 86: 2899-2902
        • Djousse L.
        • Padilla H.
        • Nelson T.L.
        • Gaziano J.M.
        • Mukamal K.J.
        Diet and metabolic syndrome.
        Endocr Metab Immune Disord Drug Targets. 2010; 10: 124-137
        • Tortosa A.
        • Bes-Rastrollo M.
        • Sanchez-Villegas A.
        • Basterra-Gortari F.J.
        • Nunez-Cordoba J.M.
        • Martinez-Gonzalez M.A.
        Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN prospective cohort.
        Diabetes Care. 2007; 30: 2957-2959
        • de Lorgeril M.
        • Salen P.
        • Martin J.L.
        • Monjaud I.
        • Delaye J.
        • Mamelle N.
        Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
        Circulation. 1999; 99: 779-785
        • Schwingshackl L.
        • Hoffmann G.
        Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials.
        Nutr Metab Cardiovasc Dis. 2014; 24: 929-939
        • Scoditti E.
        • Calabriso N.
        • Massaro M.
        • et al.
        Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer.
        Arch Biochem Biophys. 2012; 527: 81-89
        • Calton E.K.
        • James A.P.
        • Pannu P.K.
        • Soares M.J.
        Certain dietary patterns are beneficial for the metabolic syndrome: reviewing the evidence.
        Nutr Res. 2014; 34: 559-568
        • Esposito K.
        • Marfella R.
        • Ciotola M.
        • et al.
        Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial.
        JAMA. 2004; 292: 1440-1446
        • Azadbakht L.
        • Mirmiran P.
        • Esmaillzadeh A.
        • Azizi T.
        • Azizi F.
        Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome.
        Diabetes Care. 2005; 28: 2823-2831
        • Golbidi S.
        • Laher I.
        Exercise induced adipokine changes and the metabolic syndrome.
        J Diabetes Res. 2014; 2014: 726861
        • Luquet S.
        • Lopez-Soriano J.
        • Holst D.
        • et al.
        Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability.
        FASEB Journal. 2003; 17: 2299-2301
        • Takahashi S.
        • Tanaka T.
        • Sakai J.
        New therapeutic target for metabolic syndrome: PPARdelta.
        Endocr J. 2007; 54: 347-357
        • Oliver Jr., W.R.
        • Shenk J.L.
        • Snaith M.R.
        • et al.
        A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport.
        Proc Natl Acad Sci U S A. 2001; 98: 5306-5311
        • van der Veen J.N.
        • Kruit J.K.
        • Havinga R.
        • et al.
        Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1.
        J Lipid Res. 2005; 46: 526-534
        • Sprecher D.L.
        • Massien C.
        • Pearce G.
        • et al.
        Triglyceride: high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.
        Arterioscler Thromb Vasc Biol. 2007; 27: 359-365
        • Kang K.
        • Hatano B.
        • Lee C.H.
        PPAR delta agonists and metabolic diseases.
        Curr Atheroscler Rep. 2007; 9: 72-77
        • Hamblin M.
        • Chang L.
        • Fan Y.
        • Zhang J.
        • Chen Y.E.
        PPARs and the cardiovascular system.
        Antioxid Redox Signal. 2009; 11: 1415-1452
        • Varady K.A.
        • Jones P.J.
        Combination diet and exercise interventions for the treatment of dyslipidemia: an effective preliminary strategy to lower cholesterol levels?.
        J Nutr. 2005; 135: 1829-1835
        • Shaw K.
        • Gennat H.
        • O'Rourke P.
        • Del Mar C.
        Exercise for overweight or obesity.
        Cochrane Database Syst Rev. 2006; : CD003817
        • Miller M.
        • Stone N.J.
        • Ballantyne C.
        • et al.
        Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association.
        Circulation. 2011; 123: 2292-2333
        • Welty F.K.
        The contribution of triglycerides and triglyceride-rich lipoproteins to atherosclerosis. Braunwald textbook of preventive cardiology.
        1st ed. Elsevier, Philadelphia2011
        • De Caterina R.
        n-3 fatty acids in cardiovascular disease.
        N Engl J Med. 2011; 364: 2439-2450
        • Harris W.S.
        • Connor W.E.
        • Illingworth D.R.
        • Rothrock D.W.
        • Foster D.M.
        Effects of fish oil on VLDL triglyceride kinetics in humans.
        J Lipid Res. 1990; 31: 1549-1558
        • Durrington P.N.
        • Bhatnagar D.
        • Mackness M.I.
        • et al.
        An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
        Heart. 2001; 85: 544-548
        • von Schacky C.
        A review of omega-3 ethyl esters for cardiovascular prevention and treatment of increased blood triglyceride levels.
        Vasc Health Risk Manag. 2006; 2: 251-262
        • Nestel P.J.
        • Connor W.E.
        • Reardon M.F.
        • Connor S.
        • Wong S.
        • Boston R.
        Suppression by diets rich in fish oil of very low density lipoprotein production in man.
        J Clin Invest. 1984; 74: 82-89
        • Jump D.B.
        • Botolin D.
        • Wang Y.
        • Xu J.
        • Demeure O.
        • Christian B.
        Docosahexaenoic acid (DHA) and hepatic gene transcription.
        Chem Phys Lipids. 2008; 153: 3-13
        • Jump D.B.
        N-3 polyunsaturated fatty acid regulation of hepatic gene transcription.
        Curr Opin Lipidol. 2008; 19: 242-247
        • Massaro M.
        • Habib A.
        • Lubrano L.
        • et al.
        The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition.
        Proc Natl Acad Sci U S A. 2006; 103: 15184-15189
        • De Caterina R.
        • Massaro M.
        Omega-3 fatty acids and the regulation of expression of endothelial pro-atherogenic and pro-inflammatory genes.
        J Membr Biol. 2005; 206: 103-116
        • Matsumoto M.
        • Sata M.
        • Fukuda D.
        • et al.
        Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice.
        Atherosclerosis. 2008; 197: 524-533
        • Prostek A.
        • Gajewska M.
        • Kamola D.
        • Balasinska B.
        The influence of EPA and DHA on markers of inflammation in 3T3-L1 cells at different stages of cellular maturation.
        Lipids Health Dis. 2014; 13: 3
        • Sinclair H.M.
        Deficiency of essential fatty acids and atherosclerosis, etcetera.
        Lancet. 1956; 270: 381-383
        • Endres S.
        • Ghorbani R.
        • Kelley V.E.
        • et al.
        The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.
        N Engl J Med. 1989; 320: 265-271
        • Calder P.C.
        Immunomodulation by omega-3 fatty acids.
        Prostaglandins Leukot Essent Fatty Acids. 2007; 77: 327-335
        • Kelley D.S.
        • Siegel D.
        • Fedor D.M.
        • Adkins Y.
        • Mackey B.E.
        DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men.
        J Nutr. 2009; 139: 495-501
        • Flachs P.
        • Mohamed-Ali V.
        • Horakova O.
        • et al.
        Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet.
        Diabetologia. 2006; 49: 394-397
        • Ichimura A.
        • Hirasawa A.
        • Poulain-Godefroy O.
        • et al.
        Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.
        Nature. 2012; 483: 350-354
        • Oh D.Y.
        • Talukdar S.
        • Bae E.J.
        • et al.
        GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.
        Cell. 2010; 142: 687-698
        • De Caterina R.
        • Madonna R.
        • Bertolotto A.
        • Schmidt E.B.
        n-3 fatty acids in the treatment of diabetic patients: biological rationale and clinical data.
        Diabetes Care. 2007; 30: 1012-1026
        • Flachs P.
        • Rossmeisl M.
        • Kopecky J.
        The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity.
        Physiol Res. 2014; 63: S93-118
        • Calder P.C.
        Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?.
        Br J Clin Pharmaco. 2013; 75: 645-662
        • Titos E.
        • Rius B.
        • Gonzalez-Periz A.
        • et al.
        Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype.
        J Immunol. 2011; 187: 5408-5418
        • Tang Y.
        • Zhang M.J.
        • Hellmann J.
        • Kosuri M.
        • Bhatnagar A.
        • Spite M.
        Proresolution therapy for the treatment of delayed healing of diabetic wounds.
        Diabetes. 2013; 62: 618-627
        • Demetz E.
        • Schroll A.
        • Auer K.
        • et al.
        The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism.
        Cell Metab. 2014; 20: 787-798
        • Geleijnse J.M.
        • Giltay E.J.
        • Grobbee D.E.
        • Donders A.R.
        • Kok F.J.
        Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials.
        J Hypertens. 2002; 20: 1493-1499
        • Goodfellow J.
        • Bellamy M.F.
        • Ramsey M.W.
        • Jones C.J.
        • Lewis M.J.
        Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia.
        J Am Coll Cardiol. 2000; 35: 265-270
        • Miller P.E.
        • Van Elswyk M.
        • Alexander D.D.
        Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials.
        America. 2014; 27: 885-896
        • Engler M.B.
        Vascular relaxation to omega-3 fatty acids: comparison to sodium nitroprusside, nitroglycerin, papaverine, and D600.
        Cardiovasc Drugs Ther. 1992; 6: 605-610
        • Ianiro G.
        • Franceschi F.
        • Bibbo S.
        • Gasbarrini A.
        Omega-3 fatty acids: a novel resort against gastrointestinal injury.
        Eur Rev Med Pharmacol Sci. 2014; 18: 3086-3090
        • Inaba Y.
        • Chen J.A.
        • Bergmann S.R.
        Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.
        Int J Cardiovasc Imaging. 2010; 26: 631-640
        • Feron O.
        • Dessy C.
        • Moniotte S.
        • Desager J.P.
        • Balligand J.L.
        Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.
        J Clin Invest. 1999; 103: 897-905
        • Wang T.M.
        • Chen C.J.
        • Lee T.S.
        • et al.
        Docosahexaenoic acid attenuates VCAM-1 expression and NF-kappaB activation in TNF-alpha-treated human aortic endothelial cells.
        J Nutral biochemistry. 2011; 22: 187-194
        • Layne J.
        • Majkova Z.
        • Smart E.J.
        • Toborek M.
        • Hennig B.
        Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases.
        J Nutr Biochem. 2011; 22: 807-811
        • Kiecolt-Glaser J.K.
        • Belury M.A.
        • Andridge R.
        • Malarkey W.B.
        • Hwang B.S.
        • Glaser R.
        Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial.
        Brain. 2012; 26: 988-995
        • Bouwens M.
        • van de Rest O.
        • Dellschaft N.
        • et al.
        Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells.
        Am J Clin Nutr. 2009; 90: 415-424
        • Lee T.C.
        • Ivester P.
        • Hester A.G.
        • et al.
        The impact of polyunsaturated fatty acid-based dietary supplements on disease biomarkers in a metabolic syndrome/diabetes population.
        Lipids Health Dis. 2014; 13: 196
        • Brown J.M.
        • Chung S.
        • Sawyer J.K.
        • et al.
        Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2010; 30: 24-30
        • Brown A.L.
        • Zhu X.
        • Rong S.
        • et al.
        Omega-3 fatty acids ameliorate atherosclerosis by favorably altering monocyte subsets and limiting monocyte recruitment to aortic lesions.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2122-2130
        • Degirolamo C.
        • Kelley K.L.
        • Wilson M.D.
        • Rudel L.L.
        Dietary n-3 LCPUFA from fish oil but not alpha-linolenic acid-derived LCPUFA confers atheroprotection in mice.
        J Lipid Res. 2010; 51: 1897-1905
        • Nakajima K.
        • Yamashita T.
        • Kita T.
        • et al.
        Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor-deficient mice.
        Arterioscler Thromb Vasc Biol. 2011; 31: 1963-1972
        • Mozaffarian D.
        • Lemaitre R.N.
        • King I.B.
        • et al.
        Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.
        Ann Intern Med. 2013; 158: 515-525
        • Amano T.
        • Matsubara T.
        • Uetani T.
        • et al.
        Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study.
        Atherosclerosis. 2011; 218: 110-116
        • Casula M.
        • Soranna D.
        • Catapano A.L.
        • Corrao G.
        Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, placebo controlled trials.
        Atheroscler Suppl. 2013; 14 ([corrected]): 243-251
        • de Oliveira Otto M.C.
        • Wu J.H.
        • Baylin A.
        • et al.
        Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the multi-ethnic study of atherosclerosis.
        J Am Heart Assoc. 2013; 2: e000506
      1. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
        Lancet. 1999; 354: 447-455
        • Yokoyama M.
        • Origasa H.
        • Matsuzaki M.
        • et al.
        Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
        Lancet. 2007; 369: 1090-1098
        • Salman Azhar G.K.
        PPARα: its role in the human metabolic syndrome.
        Future Lipidol. 2007; 2: 31-53
        • Duval C.
        • Muller M.
        • Kersten S.
        PPARalpha and dyslipidemia.
        Biochim Biophys Acta. 2007; 1771: 961-971
        • Moraes L.A.
        • Piqueras L.
        • Bishop-Bailey D.
        Peroxisome proliferator-activated receptors and inflammation.
        Pharmacol Ther. 2006; 110: 371-385
        • Robinson E.
        • Grieve D.J.
        Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease.
        Pharmacol Ther. 2009; 122: 246-263
        • Brown J.D.
        • Plutzky J.
        Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets.
        Circulation. 2007; 115: 518-533
        • Chinetti-Gbaguidi G.
        • Rigamonti E.
        • Helin L.
        • et al.
        Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages.
        J Lipid Res. 2005; 46: 2717-2725
        • Frick M.H.
        • Elo O.
        • Haapa K.
        • et al.
        Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
        N Engl J Med. 1987; 317: 1237-1245
        • Scott R.
        • O'Brien R.
        • Fulcher G.
        • et al.
        Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
        Diabetes Care. 2009; 32: 493-498
        • Group A.S.
        • Ginsberg H.N.
        • Elam M.B.
        • et al.
        Effects of combination lipid therapy in type 2 diabetes mellitus.
        N Engl J Med. 2010; 362: 1563-1574
        • Gaudet D.
        • Brisson D.
        • Tremblay K.
        • et al.
        Targeting APOC3 in the familial chylomicronemia syndrome.
        N Engl J Med. 2014; 371: 2200-2206
        • Graham M.J.
        • Lee R.G.
        • Bell 3rd, T.A.
        • et al.
        Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.
        Circ Res. 2013; 112: 1479-1490
        • Group H.T.C.
        • Landray M.J.
        • Haynes R.
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N Engl J Med. 2014; 371: 203-212
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N Engl J Med. 2007; 357: 2109-2122
        • Investigators A.-H.
        • Boden W.E.
        • Probstfield J.L.
        • et al.
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N Engl J Med. 2011; 365: 2255-2267
        • Takagi H.
        • Niwa M.
        • Mizuno Y.
        • Goto S.N.
        • Umemoto T.
        • Group A.
        Telmisartan as a metabolic sartan: the first meta-analysis of randomized controlled trials in metabolic syndrome.
        J Am Soc Hypertens. 2013; 7: 229-235
        • Xie Q.W.
        • Kashiwabara Y.
        • Nathan C.
        Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase.
        J Biol Chem. 1994; 269: 4705-4708
        • Yamamoto K.
        • Arakawa T.
        • Ueda N.
        • Yamamoto S.
        Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells.
        J Biol Chem. 1995; 270: 31315-31320
        • Ruiz-Ortega M.
        • Lorenzo O.
        • Ruperez M.
        • Konig S.
        • Wittig B.
        • Egido J.
        Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms.
        Circ Res. 2000; 86: 1266-1272
        • Zhou M.S.
        • Schulman I.H.
        • Zeng Q.
        Link between the renin-angiotensin system and insulin resistance: implications for cardiovascular disease.
        Vascular medicine. 2012; 17: 330-341
        • Velloso L.A.
        • Folli F.
        • Sun X.J.
        • White M.F.
        • Saad M.J.
        • Kahn C.R.
        Cross-talk between the insulin and angiotensin signaling systems.
        Proc Natl Acad Sci U S A. 1996; 93: 12490-12495
        • Taniyama Y.
        • Hitomi H.
        • Shah A.
        • Alexander R.W.
        • Griendling K.K.
        Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1142-1147
        • Andreozzi F.
        • Laratta E.
        • Sciacqua A.
        • Perticone F.
        • Sesti G.
        Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells.
        Circ Res. 2004; 94: 1211-1218
        • Shimamoto K.
        • Hirata A.
        • Fukuoka M.
        • et al.
        Insulin sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive patients.
        Hypertension. 1994; 23: I29-33
        • Sharma A.M.
        • Janke J.
        • Gorzelniak K.
        • Engeli S.
        • Luft F.C.
        Angiotensin blockade prevents type 2 diabetes by formation of fat cells.
        Hypertension. 2002; 40: 609-611
        • Rizos C.V.
        • Elisaf M.S.
        Antihypertensive drugs and glucose metabolism.
        World J Cardiol. 2014; 6: 517-530
        • Pollare T.
        • Lithell H.
        • Berne C.
        A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension.
        N Engl J Med. 1989; 321: 868-873
        • Arauz-Pacheco C.
        • Ramirez L.C.
        • Rios J.M.
        • Raskin P.
        Hypoglycemia induced by angiotensin-converting enzyme inhibitors in patients with non-insulin-dependent diabetes receiving sulfonylurea therapy.
        Am J Med. 1990; 89: 811-813
        • Herings R.M.
        • de Boer A.
        • Stricker B.H.
        • Leufkens H.G.
        • Porsius A.
        Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme.
        Lancet. 1995; 345: 1195-1198
        • Ohshima K.
        • Mogi M.
        • Nakaoka H.
        • et al.
        Possible role of angiotensin-converting enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1-7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade.
        Hypertension. 2014; 63: e53-e59
        • Platten M.
        • Youssef S.
        • Hur E.M.
        • et al.
        Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.
        Proc Natl Acad Sci U S A. 2009; 106: 14948-14953
        • Xu X.
        • Niu Y.
        • Liang K.
        • Wang J.
        • Li X.
        • Yang Y.
        Heat shock transcription factor delta is targeted for degradation via an ubiquitin-like protein ThiS in Escherichia coli.
        Biochem Biophys Res Commun. 2015;
        • Dasu M.R.
        • Riosvelasco A.C.
        • Jialal I.
        Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo.
        Atherosclerosis. 2009; 202: 76-83
        • Engeli S.
        • Bohnke J.
        • Gorzelniak K.
        • et al.
        Weight loss and the renin-angiotensin-aldosterone system.
        Hypertension. 2005; 45: 356-362
        • Tuck M.L.
        • Sowers J.
        • Dornfeld L.
        • Kledzik G.
        • Maxwell M.
        The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients.
        N Engl J Med. 1981; 304: 930-933
        • Kouyama R.
        • Suganami T.
        • Nishida J.
        • et al.
        Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor.
        Endocrinology. 2005; 146: 3481-3489
        • Yvan-Charvet L.
        • Even P.
        • Bloch-Faure M.
        • et al.
        Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.
        Diabetes. 2005; 54: 991-999
        • Brown N.J.
        Aldosterone and vascular inflammation.
        Hypertension. 2008; 51: 161-167
        • Caprio M.
        • Feve B.
        • Claes A.
        • Viengchareun S.
        • Lombes M.
        • Zennaro M.C.
        Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis.
        FASEB J. 2007; 21: 2185-2194
        • Guo C.
        • Ricchiuti V.
        • Lian B.Q.
        • et al.
        Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines.
        Circulation. 2008; 117: 2253-2261
        • Caprio M.
        • Newfell B.G.
        • la Sala A.
        • et al.
        Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion.
        Circ Res. 2008; 102: 1359-1367
        • Calle C.
        • Campion J.
        • Garcia-Arencibia M.
        • Maestro B.
        • Davila N.
        Transcriptional inhibition of the human insulin receptor gene by aldosterone.
        J Steroid Biochem Mol Biol. 2003; 84: 543-553
        • Hirata A.
        • Maeda N.
        • Hiuge A.
        • et al.
        Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice.
        Cardiovasc Res. 2009; 84: 164-172
        • Hitomi H.
        • Kiyomoto H.
        • Nishiyama A.
        • et al.
        Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells.
        Hypertension. 2007; 50: 750-755
        • Wada T.
        • Kenmochi H.
        • Miyashita Y.
        • et al.
        Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet.
        Endocrinology. 2010; 151: 2040-2049
        • Sato A.
        • Fukuda S.
        Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension.
        J Hum Hypertens. 2010; 24: 387-394
        • Zannad F.
        • McMurray J.J.
        • Krum H.
        • et al.
        Eplerenone in patients with systolic heart failure and mild symptoms.
        N Engl J Med. 2011; 364: 11-21
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        • Cholesterol Treatment Trialists C
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Tousoulis D.
        • Psarros C.
        • Demosthenous M.
        • Patel R.
        • Antoniades C.
        • Stefanadis C.
        Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins.
        J Am Coll Cardiol. 2014; 63: 2491-2502
        • Methe H.
        • Kim J.O.
        • Kofler S.
        • Nabauer M.
        • Weis M.
        Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1439-1445
        • Stoll L.L.
        • Denning G.M.
        • Weintraub N.L.
        Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease.
        Curr Pharm Des. 2006; 12: 4229-4245
        • Niessner A.
        • Steiner S.
        • Speidl W.S.
        • et al.
        Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo.
        Atherosclerosis. 2006; 189: 408-413
        • Wolfrum S.
        • Jensen K.S.
        • Liao J.K.
        Endothelium-dependent effects of statins.
        Arterioscler Thromb Vasc Biol. 2003; 23: 729-736
        • Tousoulis D.
        • Antoniades C.
        • Stefanadis C.
        Assessing inflammatory status in cardiovascular disease.
        Heart. 2007; 93: 1001-1007
        • Freeman D.J.
        • Norrie J.
        • Sattar N.
        • et al.
        Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
        Circulation. 2001; 103: 357-362
        • Sattar N.
        • Preiss D.
        • Murray H.M.
        • et al.
        Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
        Lancet. 2010; 375: 735-742
        • Chan D.C.
        • Pang J.
        • Watts G.F.
        Pathogenesis and management of the diabetogenic effect of statins: a role for adiponectin and coenzyme Q10?.
        Curr Atheroscler Rep. 2015; 17: 472
        • Nakata M.
        • Nagasaka S.
        • Kusaka I.
        • Matsuoka H.
        • Ishibashi S.
        • Yada T.
        Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control.
        Diabetologia. 2006; 49: 1881-1892
        • Devaraj S.
        • Siegel D.
        • Jialal I.
        Simvastatin (40 mg/day), adiponectin levels, and insulin sensitivity in subjects with the metabolic syndrome.
        Am J Cardiol. 2007; 100: 1397-1399
        • Forst T.
        • Pfutzner A.
        • Lubben G.
        • et al.
        Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk–the PIOSTAT Study.
        Metabolism. 2007; 56: 491-496
        • Chen Y.
        • Ohmori K.
        • Mizukawa M.
        • et al.
        Differential impact of atorvastatin vs pravastatin on progressive insulin resistance and left ventricular diastolic dysfunction in a rat model of type II diabetes.
        Circ J. 2007; 71: 144-152
        • Ates O.
        • Bilen H.
        • Keles S.
        • et al.
        Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy.
        Int J Ophthalmol. 2013; 6: 675-679
        • McCarty M.F.
        Can correction of sub-optimal coenzyme Q status improve beta-cell function in type II diabetics?.
        Med Hypotheses. 1999; 52: 397-400
        • Maechler P.
        • Li N.
        • Casimir M.
        • Vetterli L.
        • Frigerio F.
        • Brun T.
        Role of mitochondria in beta-cell function and dysfunction.
        Adv Exp Med Biol. 2010; 654: 193-216
        • Littarru G.P.
        • Langsjoen P.
        Coenzyme Q10 and statins: biochemical and clinical implications.
        Mitochondrion. 2007; 7: S168-S174