title: C-C chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model.
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.
authors: Department of Medicine, Graduate School, Yonsei University, Wonju, Korea.
authors: Hong-Min
authors: HM
authors: Kim
authors: Department of Medicine, Graduate School, Yonsei University, Wonju, Korea.
authors: Eun Soo
authors: ES
authors: Lee
authors: College of Pharmacy, Kangwon National University, Chuncheon, Korea.
authors: Bo Ra
authors: BR
authors: Lee
authors: Department of Medicine, Graduate School, Yonsei University, Wonju, Korea.
authors: Dhananjay
authors: D
authors: Yadav
authors: Department of Medicine, Graduate School, Yonsei University, Wonju, Korea.
authors: You Mi
authors: YM
authors: Kim
authors: College of Pharmacy, Kangwon National University, Chuncheon, Korea.
authors: Hyun-Jeong
authors: HJ
authors: Ko
authors: Department of Physiology, Graduate School, Yonsei University, Wonju, Korea; Institute of Lifestyle Medicine, Yonsei University, Wonju, Korea.
authors: Kyu Sang
authors: KS
authors: Park
authors: Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.
authors: Eun Young
authors: EY
authors: Lee
authors: Department of Medicine, Graduate School, Yonsei University, Wonju, Korea; Institute of Lifestyle Medicine, Yonsei University, Wonju, Korea.
authors: Choon Hee
authors: CH
authors: Chung
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005951:Glucose Tolerance Test; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048588:Benzoxazines; D010880:Piperidines; D012333:RNA, Messenger; C573791:RS 102895; D054390:Receptors, CCR2