C-C Chemokine Receptor 2 Inhibitor Ameliorates Hepatic Steatosis by Improving ER Stress and Inflammation in a Type 2 Diabetic Mouse Model |
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| Authors: | Hong-Min Kim Eun Soo Lee Bo Ra Lee Dhananjay Yadav You Mi Kim Hyun-Jeong Ko Kyu Sang Park Eun Young Lee Choon Hee Chung |
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| Institution: | 1. Department of Medicine, Graduate School, Yonsei University, Wonju, Korea.; 2. College of Pharmacy, Kangwon National University, Chuncheon, Korea.; 3. Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.; 4. Department of Physiology, Graduate School, Yonsei University, Wonju, Korea.; 5. Institute of Lifestyle Medicine, Yonsei University, Wonju, Korea.; Hosptial Infantil Universitario Niño Jesús, CIBEROBN, SPAIN, |
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| Abstract: | Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus. |
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