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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere0121528
JournalPloS one
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 27 2015
Externally publishedYes

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Receptor, Melanocortin, Type 4
Eicosapentaenoic Acid
Fatty Liver
eicosapentaenoic acid
animal models
acid treatment
Liver
receptors
liver cirrhosis
mice
Crowns
liver
Liver Cirrhosis
fatty liver
hepatocytes
plasma kallikrein
Hepatocytes
Plasma Kallikrein
adipokines
transforming growth factors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice. / Konuma, Kuniha; Itoh, Michiko; Suganami, Takayoshi; Kanai, Sayaka; Nakagawa, Nobutaka; Sakai, Takeru; Kawano, Hiroyuki; Hara, Mitsuko; Kojima, Soichi; Izumi, Yuichi; Ogawa, Yoshihiro.

In: PloS one, Vol. 10, No. 3, e0121528, 27.03.2015.

Research output: Contribution to journalArticle

Konuma, K, Itoh, M, Suganami, T, Kanai, S, Nakagawa, N, Sakai, T, Kawano, H, Hara, M, Kojima, S, Izumi, Y & Ogawa, Y 2015, 'Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice', PloS one, vol. 10, no. 3, e0121528. https://doi.org/10.1371/journal.pone.0121528
Konuma, Kuniha ; Itoh, Michiko ; Suganami, Takayoshi ; Kanai, Sayaka ; Nakagawa, Nobutaka ; Sakai, Takeru ; Kawano, Hiroyuki ; Hara, Mitsuko ; Kojima, Soichi ; Izumi, Yuichi ; Ogawa, Yoshihiro. / Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice. In: PloS one. 2015 ; Vol. 10, No. 3.
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