Published online before print September 3, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.090102

Accepted for publication June 22, 2009.

Article

Tacrolimus Ameliorates Metabolic Disturbance and Oxidative Stress Caused by Hepatitis C Virus Core Protein. Analysis Using Mouse Model and Cultured Cells

Kyoji Moriya^*, Hideyuki Miyoshi^*, Takeya Tsutsumi^*, Seiko Shinzawa^*, Hajime Fujie^*, Yoshizumi Shintani^*, Hiroshi Yotsuyanagi^*, Kohji Moriishi, Yoshiharu Matsuura, Tetsuro Suzuki, Tatsuo Miyamura, and Kazuhiko Koike^*@

From the Department of Internal Medicine,* Graduate School of Medicine, University of Tokyo, Tokyo; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka; and Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: kkoike-tky{at}umin.ac.jp.

	Abstract

Hepatic steatosis and insulin resistance are factors that aggravate the progression of liver disease caused by hepatitis C virus (HCV) infection. In the pathogenesis of liver disease and metabolic disorders in HCV infection, oxidative stress due to mitochondrial respiratory chain dysfunction plays a pivotal role. Tacrolimus (FK506) is supposed to protect mitochondrial respiratory function. We studied whether tacrolimus affects the development of HCV-associated liver disease using HCV core gene transgenic mice, which develop hepatic steatosis, insulin resistance, and hepatocellular carcinoma. Administration of tacrolimus to HCV core gene transgenic mice three times per week for 3 months led to a significant reduction in the amounts of lipid in the liver as well as in serum insulin. Tacrolimus treatment also ameliorated oxidative stress and DNA damage in the liver of the core gene transgenic mice. Tacrolimus administration reproduced these effects in a dose-dependent manner in HepG2 cells expressing the core protein. The intrahepatic level of tumor necrosis factor-, which may be a key molecule for the pathogenesis in HCV infection, was significantly decreased in tacrolimus-treated core gene transgenic mice. Tacrolimus thus reversed the effect of the core protein in the pathogenesis of HCV-associated liver disease. These results may provide new therapeutic tools for chronic hepatitis C, in which oxidative stress and abnormalities in lipid and glucose metabolism contribute to liver pathogenesis.