title: Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.
abstract: Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kuniha
authors: K
authors: Konuma
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Michiko
authors: M
authors: Itoh
authors: Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency, PRESTO, Tokyo, Japan.
authors: Takayoshi
authors: T
authors: Suganami
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Sayaka
authors: S
authors: Kanai
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Nobutaka
authors: N
authors: Nakagawa
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Takeru
authors: T
authors: Sakai
authors: Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical, Shizuoka, Japan.
authors: Hiroyuki
authors: H
authors: Kawano
authors: Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
authors: Mitsuko
authors: M
authors: Hara
authors: Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
authors: Soichi
authors: S
authors: Kojima
authors: Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yuichi
authors: Y
authors: Izumi
authors: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors: Yoshihiro
authors: Y
authors: Ogawa
mesh_terms: D054392:Adipokines / Q000097:blood; D052242:Adiponectin / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency*
chemical_list: D054392:Adipokines; D052242:Adiponectin; C499919:Adipoq protein, mouse; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D015118:Eicosapentaenoic Acid