PMID- 25816330
OWN - NLM
STAT- MEDLINE
DCOM- 20160311
LR  - 20200306
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 3
DP  - 2015
TI  - Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse 
      model using melanocortin 4 receptor-deficient mice.
PG  - e0121528
LID - 10.1371/journal.pone.0121528 [doi]
LID - e0121528
AB  - 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-beta 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.
FAU - Konuma, Kuniha
AU  - Konuma K
AD  - 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.
FAU - Itoh, Michiko
AU  - Itoh M
AD  - Department of Molecular Endocrinology 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 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.
FAU - Kanai, Sayaka
AU  - Kanai S
AD  - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical 
      and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
FAU - Nakagawa, Nobutaka
AU  - Nakagawa N
AD  - Department of Molecular Endocrinology 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 - Kawano, Hiroyuki
AU  - Kawano H
AD  - Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical, 
      Shizuoka, Japan.
FAU - Hara, Mitsuko
AU  - Hara M
AD  - Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science 
      Technologies, Wako, Japan.
FAU - Kojima, Soichi
AU  - Kojima S
AD  - Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science 
      Technologies, Wako, Japan.
FAU - Izumi, Yuichi
AU  - Izumi Y
AD  - Department of Periodontology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo, 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; Japan 
      Science and Technology Agency, CREST, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150327
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adipokines)
RN  - 0 (Adiponectin)
RN  - 0 (Adipoq protein, mouse)
RN  - 0 (MC4R protein, mouse)
RN  - 0 (Receptor, Melanocortin, Type 4)
RN  - AAN7QOV9EA (Eicosapentaenoic Acid)
SB  - IM
MH  - Adipokines/blood
MH  - Adiponectin/blood
MH  - Animals
MH  - Disease Models, Animal
MH  - Eicosapentaenoic Acid/*administration & dosage/pharmacology
MH  - Liver/drug effects/pathology
MH  - Liver Cirrhosis, Experimental/pathology/*prevention & control
MH  - Mice
MH  - Mice, Knockout
MH  - Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/pathology
MH  - Receptor, Melanocortin, Type 4/*deficiency
PMC - PMC4376873
COIS- Competing Interests: Hiroyuki Kawano is an employee of Mochida Pharmaceutical Co. 
      Ltd., which funded this study and provided highly purified EPA ethyl ester. There 
      are no other potential conflicts of interest relevant to this article. This does 
      not alter the authors' adherence to PLOS ONE policies on sharing data and 
      materials.
EDAT- 2015/03/31 06:00
MHDA- 2016/03/12 06:00
PMCR- 2015/03/27
CRDT- 2015/03/28 06:00
PHST- 2014/11/13 00:00 [received]
PHST- 2015/02/03 00:00 [accepted]
PHST- 2015/03/28 06:00 [entrez]
PHST- 2015/03/31 06:00 [pubmed]
PHST- 2016/03/12 06:00 [medline]
PHST- 2015/03/27 00:00 [pmc-release]
AID - PONE-D-14-50671 [pii]
AID - 10.1371/journal.pone.0121528 [doi]
PST - epublish
SO  - PLoS One. 2015 Mar 27;10(3):e0121528. doi: 10.1371/journal.pone.0121528. 
      eCollection 2015.