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Involvement of the PA28-Dependent Pathway in Insulin Resistance Induced by Hepatitis C Virus Core Protein

Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka,¹ Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo,² Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Tokyo,³ Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan⁴

Received 4 August 2006/ Accepted 16 November 2006

The hepatitis C virus (HCV) core protein is a component of nucleocapsids and a pathogenic factor for hepatitis C. Several epidemiological and experimental studies have suggested that HCV infection is associated with insulin resistance, leading to type 2 diabetes. We have previously reported that HCV core gene-transgenic (PA28^+/+CoreTg) mice develop marked insulin resistance and that the HCV core protein is degraded in the nucleus through a PA28-dependent pathway. In this study, we examined whether PA28 is required for HCV core-induced insulin resistance in vivo. HCV core gene-transgenic mice lacking the PA28 gene (PA28^–/–CoreTg) were prepared by mating of PA28^+/+CoreTg with PA28-knockout mice. Although there was no significant difference in the glucose tolerance test results among the mice, the insulin sensitivity in PA28^–/–CoreTg mice was recovered to a normal level in the insulin tolerance test. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), production of IRS2, and phosphorylation of Akt were suppressed in the livers of PA28^+/+CoreTg mice in response to insulin stimulation, whereas they were restored in the livers of PA28^–/–CoreTg mice. Furthermore, activation of the tumor necrosis factor alpha promoter in human liver cell lines or mice by the HCV core protein was suppressed by the knockdown or knockout of the PA28 gene. These results suggest that the HCV core protein suppresses insulin signaling through a PA28-dependent pathway.

Published ahead of print on 29 November 2006.

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