title: Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein.
abstract: 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.
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murata
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Miyamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology*; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000502:physiology*; D011972:Receptor, Insulin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014758:Viral Core Proteins / Q000502:physiology*
chemical_list: D001324:Autoantigens; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C099558:Ki antigen; D010750:Phosphoproteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D014443:Tyrosine; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt; D046988:Proteasome Endopeptidase Complex