Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice

Kuniha Konuma; Michiko Itoh; Takayoshi Suganami; Sayaka Kanai; Nobutaka Nakagawa; Takeru Sakai; Hiroyuki Kawano; Mitsuko Hara; Soichi Kojima; Yuichi Izumi; Yoshihiro Ogawa

doi:10.1371/journal.pone.0121528

Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice

PLoS One. 2015 Mar 27;10(3):e0121528. doi: 10.1371/journal.pone.0121528. eCollection 2015.

Authors

Affiliations

¹ 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.
² Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ 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.
⁴ Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical, Shizuoka, Japan.
⁵ Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
⁶ Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁷ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipokines / blood
Adiponectin / blood
Animals
Disease Models, Animal
Eicosapentaenoic Acid / administration & dosage*
Eicosapentaenoic Acid / pharmacology
Liver / drug effects
Liver / pathology
Liver Cirrhosis, Experimental / pathology
Liver Cirrhosis, Experimental / prevention & control*
Mice
Mice, Knockout
Non-alcoholic Fatty Liver Disease / drug therapy*
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / pathology
Receptor, Melanocortin, Type 4 / deficiency*

Substances

Adipokines
Adiponectin
Adipoq protein, mouse
MC4R protein, mouse
Receptor, Melanocortin, Type 4
Eicosapentaenoic Acid

Grants and funding

This work was supported in part by Mochida Pharmaceutical Co. Ltd. who also provided highly purified EPA ethyl ester. Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, Japan Science and Technology Agency, Japan Society for the Promotion of Science, and research grants from Takeda Science Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Ono Medical Research Foundation, Yokoyama Foundation for Clinical Pharmacology, and The Uehara Memorial Foundation. Michiko Itoh was supported by Research Fellowship of Japan Society for the Promotion of Science. Co-author Hiroyuki Kawano is employed by Mochida Pharmaceutical Co. Ltd. Mochida Pharmaceutical Co. Ltd. provided support in the form of salary for Hiroyuki Kawano, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.