PMID- 29802399 OWN - NLM STAT- MEDLINE DCOM- 20191008 LR - 20191008 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 May 25 TI - Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis. PG - 8157 LID - 10.1038/s41598-018-26383-8 [doi] LID - 8157 AB - Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD). Treatment with OCA effectively prevented chronic inflammation and liver fibrosis in WD-fed MC4R-KO mice with only marginal effect on body weight and hepatic steatosis. Hepatic crown-like structure (hCLS) is a unique histological structure characteristic of NASH, which triggers hepatocyte death-induced interstitial fibrosis. Intriguingly, treatment with OCA markedly reduced hCLS formation even after MC4R-KO mice developed NASH, thereby inhibiting the progression of liver fibrosis. As its mechanism of action, OCA suppressed metabolic stress-induced p53 activation and cell death in hepatocytes. Our findings in this study highlight the role of FXR in hepatocytes in the pathogenesis of NASH. Collectively, this study demonstrates the anti-fibrotic effect of OCA in a murine model of NASH with obesity and insulin resistance, which suggests the clinical implication for human NASH. FAU - Goto, Toshihiro AU - Goto T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Specialty Medicine Group, Drug Development Research Laboratories, Sumitomo Dainippon Pharma. Co., Ltd, Osaka, Japan. FAU - Itoh, Michiko AU - Itoh M AD - Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Suganami, Takayoshi AU - Suganami T AD - Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. suganami@riem.nagoya-u.ac.jp. FAU - Kanai, Sayaka AU - Kanai S AD - Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Shirakawa, Ibuki AU - Shirakawa I AD - Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Sakai, Takeru AU - Sakai T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Asakawa, Masahiro AU - Asakawa M AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Yoneyama, Toshihiro AU - Yoneyama T AD - Omics Group, Genomic Science Laboratories, Sumitomo Dainippon Pharma. Co., Ltd, Osaka, Japan. FAU - Kai, Toshihiro AU - Kai T AD - Omics Group, Genomic Science Laboratories, Sumitomo Dainippon Pharma. Co., Ltd, Osaka, Japan. FAU - Ogawa, Yoshihiro AU - Ogawa Y AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. ogawa.mem@tmd.ac.jp. AD - Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. ogawa.mem@tmd.ac.jp. AD - Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. ogawa.mem@tmd.ac.jp. AD - Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ogawa.mem@tmd.ac.jp. AD - Japan Agency for Medical Research and Development, CREST, Tokyo, Japan. ogawa.mem@tmd.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180525 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (MC4R protein, mouse) RN - 0 (Receptor, Melanocortin, Type 4) RN - 0 (Tumor Suppressor Protein p53) RN - 0462Z4S4OZ (obeticholic acid) RN - 0GEI24LG0J (Chenodeoxycholic Acid) SB - IM MH - Animals MH - Body Weight/drug effects MH - Cell Death/*drug effects MH - Chenodeoxycholic Acid/*analogs & derivatives/pharmacology MH - Cytoprotection/*drug effects MH - Disease Models, Animal MH - Disease Progression MH - Gene Knockout Techniques MH - Hepatocytes/*drug effects/metabolism/*pathology MH - Insulin Resistance MH - Liver Cirrhosis/complications/pathology/*prevention & control MH - Mice MH - Mice, Inbred C57BL MH - Non-alcoholic Fatty Liver Disease/*complications MH - Obesity/complications MH - Receptor, Melanocortin, Type 4/deficiency/genetics MH - Tumor Suppressor Protein p53/metabolism PMC - PMC5970222 COIS- T.G., T.Y. and T.K. are employees of Sumitomo Dainippon Pharma. Co., Ltd. M.I. and I.S. are assigned to the Joint Research Department of Tokyo Medical and Dental University and Shionogi & Co. Ltd. EDAT- 2018/05/29 06:00 MHDA- 2019/10/09 06:00 PMCR- 2018/05/25 CRDT- 2018/05/27 06:00 PHST- 2017/09/11 00:00 [received] PHST- 2018/04/17 00:00 [accepted] PHST- 2018/05/27 06:00 [entrez] PHST- 2018/05/29 06:00 [pubmed] PHST- 2019/10/09 06:00 [medline] PHST- 2018/05/25 00:00 [pmc-release] AID - 10.1038/s41598-018-26383-8 [pii] AID - 26383 [pii] AID - 10.1038/s41598-018-26383-8 [doi] PST - epublish SO - Sci Rep. 2018 May 25;8(1):8157. doi: 10.1038/s41598-018-26383-8.