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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0087v1 198/2/309    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ito, M. Articles by Kanatani, A. Search for Related Content PubMed PubMed Citation Articles by Ito, M. Articles by Kanatani, A.

M Ito, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
A Gomori, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
J Suzuki, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
S Tsujioka, Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co.Ltd, Tsukuba, Japan
M Sasaki, Tsukuba, Japan
M Matsuda, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
M Bednarek, Medicinal Chemistry, Merck Research Laboratories, Rahway, United States
M Ito, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
A Ishihara, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
H Iwaasa, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan
D MacNeil, Metabolic Disorders, Merck Reserch Laboratories, Rahway, United States
A Kanatani, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Tsukuba, Japan

Correspondence: Akio Kanatani, Email: akio_kanatani{at}merck.com

Abstract

Blockade of brain melanin-concentrating hormone 1 receptor significantly ameliorates fatty liver as well as obesity. However, the mode of action of this effect is unknown. This study examined the effect of a melanin-concentrating hormone 1 receptor antagonist in murine steatohepatitis models with and without obesity, and clarified whether these pharmacological effects were attributed to anti-obesity effects. Steatohepatitis with concomitant obese phenotypes was developed after 52 weeks’ exposure to a high-fat diet, and steatohepatitis with reduced body weight was developed by exposure to a methionine-choline-deficient diet for 10 days. Chronic intracerebroventricular infusion of a peptidic melanin-concentrating hormone 1 receptor antagonist reduced hepatic triglyceride contents and ameliorated steatohepatitis on histological observations in both mice models. Improvement of steatohepatitis was concomitant with amelioration of obese phenotypes such as hyperinsulinemia and hyperleptinemia in the case of the obese model, whereas body weight reduction was not associated with amelioration of steatohepatitis by the antagonist in the lean model. Reduction of hepatic gene expressions encoding cytochromes P450 4A were identified by treatment with the antagonist in both the obese and lean models. These results suggest that brain blockade of melanin-concentrating hormone 1 receptor could alleviate steatohepatitis independently from anti-obesity effects. In conclusion, melanin-concentrating hormone 1 receptor antagonist could be a new therapeutic potential for the treatment of human nonalcoholic steatohepatitis.