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 (
PA28gamma(+/+)CoreTg) mice develop marked
insulin resistance and that the HCV core
protein is degraded in the nucleus through a PA28gamma-dependent pathway. In this study, we examined whether
PA28gamma is required for HCV core-induced
insulin resistance in vivo. HCV core gene-transgenic mice lacking the
PA28gamma gene (
PA28gamma(-/-)CoreTg) were prepared by mating of
PA28gamma(+/+)CoreTg with PA28gamma-knockout mice. Although there was no significant difference in the
glucose tolerance test results among the mice, the
insulin sensitivity in
PA28gamma(-/-)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
PA28gamma(+/+)CoreTg mice in response to
insulin stimulation, whereas they were restored in the livers of
PA28gamma(-/-)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
PA28gamma gene. These results suggest that the HCV core
protein suppresses
insulin signaling through a PA28gamma-dependent pathway.