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DOI: 10.1160/TH10-09-0574
Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPARα/γ activity in microvascular endothelial cells
Publikationsverlauf
Received: 08. September 2010
Accepted after major revision: 02. Juni 2011
Publikationsdatum:
24. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201103/lookinside/thumbnails/10-1160-th10-09-0574-1.jpg)
Summary
Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10−8 and 10−7 M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ± 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.
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References
- 1 Caballero AE, Arora S, Saouaf R. et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999; 48: 1856-1862.
- 2 Tooke J. Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes. J Diabetes Complications 2000; 14: 197-200.
- 3 Wong TY, Klein R, Sharrett AR. et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. J Am Med Assoc 2002; 287: 2528-2533.
- 4 Balletshofer BM, Rittig K, Enderle MD. et al. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000; 101: 1780-1784.
- 5 Endemann G, Stanton LW, Madden KS. et al. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 1993; 268: 11811-11816.
- 6 Glatz JF, Bonen A, Ouwens DM. et al. Regulation of sarcolemmal transport of substrates in the healthy and diseased heart. Cardiovasc Drugs Ther 2006; 20: 471-476.
- 7 Tandon NN, Kralisz U, Jamieson GA. Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion. J Biol Chem 1989; 264: 7576-7583.
- 8 Febbraio M, Guy E, Silverstein RL. Stem cell transplantation reveals that absence of macrophage CD36 is protective against atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 2333-2338.
- 9 Kashyap SR, Ioachimescu AG, Gornik HL. et al. Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL. Obesity (Silver Spring) 2009; 17: 2142-2148.
- 10 Ouwens DM, Diamant M, Fodor M. et al. Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification. Diabetologia 2007; 50: 1938-1948.
- 11 Pietsch A, Weber C, Goretzki M. et al. N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. Cell Biochem Funct 1995; 13: 211-216.
- 12 Clerk LH, Rattigan S, Clark MG. Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes 2002; 51: 1138-1145.
- 13 Youd JM, Rattigan S, Clark MG. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes 2000; 49: 1904-1909.
- 14 Clark MG, Wallis MG, Barrett EJ. et al. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab 2003; 284: E241-258.
- 15 Nozaki S, Kashiwagi H, Yamashita S. et al. Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J Clin Invest 1995; 96: 1859-1865.
- 16 Kunjathoor VV, Febbraio M, Podrez EA. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 2002; 277: 49982-49988.
- 17 Mitra N, Sinha S, Ramya TN. et al. N-linked oligosaccharides as outfitters for glycoprotein folding, form and function. Trends Biochem Sci 2006; 31: 156-163.
- 18 Madonna R, Di Napoli P, Massaro M. et al. Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts. J Biol Chem 2005; 280: 13503-13511.
- 19 Carluccio MA, Siculella L, Ancora MA. et al. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol 2003; 23: 622-629.
- 20 Tontonoz P, Nagy L, Alvarez JG. et al. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998; 93: 241-252.
- 21 Lee JY, Hwang DH. Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated receptors in a colon tumor cell line. Biochem Biophys Res Commun 2002; 298: 667-674.
- 22 Madonna R, Pandolfi A, Massaro M. et al. Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase. Diabetologia 2004; 47: 532-536.
- 23 Madonna R, Massaro M, Pandolfi A. et al. The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells. Int J Immunopathol Pharmacol 2007; 20: 539-555.
- 24 Madonna R, Massaro M, De Caterina R. Insulin potentiates cytokine-induced VCAM-1 expression in human endothelial cells. Biochim Biophys Acta 2008; 1782: 511-516.
- 25 Madonna R, De Caterina R. Prolonged exposure to high insulin impairs the endothelial PI3-kinase/Akt/nitric oxide signalling. Thromb Haemost 2009; 101: 345-350.
- 26 Lee J, Pilch PF. The insulin receptor: structure, function, and signaling. Am J Physiol 1994; 266: C319-334.
- 27 Saad MF, Knowler WC, Pettitt DJ. et al. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet 1989; 1: 1356-1359.
- 28 Burr ML, Fehily AM, Gilbert JF. et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989; 2: 757-761.
- 29 De Caterina R, Cybulsky MI, Clinton SK. et al. The omega-3 fatty acid docosahex-aenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb 1994; 14: 1829-1836.
- 30 Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997; 94: 4312-4317.
- 31 Thoennes SR, Tate PL, Price TM, Kilgore MW. Differential transcriptional activation of peroxisome proliferator-activated receptor gamma by omega-3 and omega-6 fatty acids in MCF-7 cells. Mol Cell Endocrinol 2000; 160: 67-73.
- 32 Vallve JC, Uliaque K, Girona J. et al. Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages. Atherosclerosis 2002; 164: 45-56.
- 33 Boudreau MD, Sohn KH, Rhee SH. et al. Suppression of tumor cell growth both in nude mice and in culture by n-3 polyunsaturated fatty acids: mediation through cyclooxygenase-independent pathways. Cancer Res 2001; 61: 1386-1391.
- 34 Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000; 405: 421-424.
- 35 Camp HS, Tafuri SR. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem 1997; 272: 10811-10816.
- 36 Hu E, Kim JB, Sarraf P. et al. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 1996; 274: 2100-2103.
- 37 Zhang B, Berger J, Zhou G. et al. Insulin-and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem 1996; 271: 31771-31774.
- 38 Rosen ED, Walkey CJ, Puigserver P. et al. Transcriptional regulation of adipogenesis. Genes Dev 2000; 14: 1293-1307.
- 39 Cagen LM, Deng X, Wilcox HG. et al. Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem J 2005; 385: 207-216.
- 40 Howell G, 3rd Deng X, Yellaturu C. et al. N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRalpha. Biochim Biophys Acta 2009; 1791: 1190-1196.
- 41 Oh da Y, Talukdar S, Bae EJ. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010; 142: 687-698.