RIP140 is Associated with Subclinical Inflammation in Type 2 Diabetic Patients

Abstract

Aims:

To evaluate the expression level of RIP140 (receptor interaction protein 140) and its correlation with inflammatory cytokine production and free fatty acids (FFAs) in type 2 diabetes.

Methods:

Plasma and peripheral blood mononuclear cells (PBMCs) were collected from 24 diabetic and 30 healthy individuals. The levels of FFAs, TC, TG, HDL-C, LDL-C, FIN, and FBG were measured. The insulin resistance index was calculated using the homeostasis model assessment (HOMA). Additionally, PBMCs from control group were cultured alone or with 500 μmol/L palmitic acid (PA). Levels of RIP140 TNF-α, and IL-6 in PBMCs were analyzed using real-time RT-PCR, Western blots and ELISA. The relationship between RIP140 and other variables was performed using SPSS 11.5 software.

Results:

TG, LDL-C, FIN, FBG, HOMA, and HDL-C were significantly different between diabetic patients and the control group. Levels of RIP140, TNF-α, and IL-6 were higher in the diabetic group compared to control. RIP140 expression was positively correlated with FFAs, HDL-c, TNF-α, IL-6, FIN, FBG, and HOMA. Finally, 500 μmol/L PA treatment increased RIP140 expression and the secretion of inflammatory cytokines in cultured control PBMCs.

Conclusions:

Increased RIP140 level may be closely associated with inflammation and disorder of lipid and glucose metabolism in diabetic patients.

Key words

diabetes - inflammatory cytokines - RIP140

* 

^* Both Authors (Junli Xue and Hongli Zhao) contributed equally to this study.

• References

• 1 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107
• 2 Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010; 61: 301-316
• 3 Tajiri Y, Mimura K, Umeda F. High-sensitivity C-reactive protein in Japanese patients with type 2 diabetes. Obes Res 2005; 13: 1810-1816
• 4 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111-1119
• 5 Cai D, Yuan M, Frantz DF et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11: 183-190
• 6 Duncan BB, Schmidt MI, Pankow JS et al. Low-Grade Systemic Inflammation and the development of type 2 Diabetes. Diabetes 2003; 52: 1799-1805
• 7 Nguyen MT, Favelyukis S, Nguyen AK 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
• 8 Schulman IG. Nuclear receptors as drug targets for metabolic disease. Adv Drug Deli Rev 2010; 62: 1307-1315
• 9 Handschin C, Spiegelman BM. The role of exercise and PGC-1 alpha in inflammation and chronic disease. Nature 2008; 454: 463-469
• 10 Mootha VK, Lindgren CM, Eriksson KF et al. PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267-273
• 11 Handschin CC, Choi CS, Chin S et al. Abnormal glucose homeostasis in skeletal muscle-specific PGC-1 alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 2007; 117: 3463-3474
• 12 Rosell M, Jones MC, Parker MG. Role of nuclear receptor corepressor RIP140 in metabolic syndrome. Biochim Biophys Acta 2011; 1812: 919-928
• 13 Cavailles V, Dauvois S, Danielian PS et al. Interaction of proteins with transcriptionally active estrogen receptors. Proc Natl Acad Sci USA 1994; 91: 10009-10013
• 14 Leonardsson G, Steel JH, Christian M et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci USA 2004; 101: 8437-8442
• 15 Seth A, Steel JH, Nichol D et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 2007; 6: 236-245
• 16 Herzog B, Hallberg M, Seth A et al. The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor. Mol Endocrinol 2007; 21: 2687-2697
• 17 Zschiedrich I, Hardeland U, Krones-Herzig A et al. Coactivator function of RIP140 for NF-kappa B/rela-dependent cytokine gene expression. Blood 2008; 112: 264-276
• 18 Ho PC, Tsui YC, Feng XD et al. NF-kappa B-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 2012; 13: 379-386
• 19 Ho PC, Chang KC, Chuang YS et al. Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. FASEB J 2011; 25: 1758-1766
• 20 Catalan V, Gómez-Ambrosi J, Lizanzu A et al. RIP140 gene and protein expression levels are downregulated in visceral adipose tissue in human morbid obesity. Obes Surg 2009; 19: 771-776
• 21 Patti ME, Butte AJ, Crunkhorn S et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 2003; 100: 8466-8471
• 22 Hallberg M, Morganstein DL, Kiskinis E et al. A functional interaction between RIP140 and PGC-1α regulates the expression of the lipid droplet protein CIDEA. Mol Cell Biol 2008; 28: 6785-6795
• 23 Ghanim H, Aljada A, Hofmeyer D et al. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004; 110: 1564-1571
• 24 Sheu WH, Chang TM, Lee WJ et al. Effect of weight loss on proinflammatory state of mononuclear cells in obese women. Obesity 2008; 16: 1033-1038
• 25 Weisberg SP, McCann D, Desai M et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
• 26 Cousin SP, Hüql SR, Wrede CE et al. Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic β-cell line INS-1. Endocrinology 2001; 142: 229-240
• 27 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402-408
• 28 Mejhert N, Laurencikiene J, Pettersson AT et al. Role of Receptor-Interacting Protein 140 in human fat cells. BMC Endocr Disord 2010; 10: 1-8
• 29 Powelka AM, Seth A, Virbasius JV et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest 2006; 116: 125-136
• 30 Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22
• 31 Olefsky JM, Glass CK. Macrophages, inflammation, and insulin Resistance. Annu Rev Physiol 2010; 72: 219-246
• 32 Mirza S, Hossain M, Mathews C et al. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: A cross-sectional study. Cytokine 2012; 57: 136-142
• 33 Ghanim H, Aljada A, Daoud N et al. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Diabetologia 2007; 50: 278-285
• 34 Kim F, Pham M, Luttrell I et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 2007; 100: 1589-1596
• 35 Huang Y, Liu J, Xu Y et al. Reduction of insulin resistance in HepG2 cells by knockdown of LITAF expression in human THP-1 macrophages. J Huazhong Univ Sci Technolog Med Sci 2012; 32: 53-58
• 36 Tripathy D, Mohanty P, Dhindsa S et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003; 52: 2882-2887