Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein.
Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein.
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DOI：
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发表时间：
2007
影响因子：
5.4
通讯作者：
Hironobu Miyamoto;K. Moriishi;K. Moriya;S. Murata;Keiji Tanaka;Tetsuro Suzuki;T. Miyamura;K. Koike;Y. Matsuura
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作者：
Hironobu Miyamoto;K. Moriishi;K. Moriya;S. Murata;Keiji Tanaka;Tetsuro Suzuki;T. Miyamura;K. Koike;Y. Matsuura
丙型肝炎病毒（HCV）核心蛋白是核衣壳的组成部分，也是丙型肝炎的致病因子。一些流行病学和实验研究表明，HCV感染与胰岛素抵抗有关，导致2型糖尿病。我们以前曾报道过，HCV核心基因转基因（PA 28 γ（+/+）CoreTg）小鼠出现明显的胰岛素抵抗，并且HCV核心蛋白通过PA 28 γ依赖性途径在细胞核中降解。在这项研究中，我们研究了PA 28 γ是否需要在体内HCV核心诱导的胰岛素抵抗。通过将PA 28 γ（+/+）CoreTg与PA 28 γ敲除小鼠交配，制备缺乏PA 28 γ基因的HCV核心基因转基因小鼠（PA 28 γ（-/-）CoreTg）。虽然小鼠之间的葡萄糖耐量试验结果没有显著差异，但在胰岛素耐量试验中，PA 28 γ（-/-）CoreTg小鼠的胰岛素敏感性恢复到正常水平。胰岛素刺激后，PA 28 γ（+/+）CoreTg小鼠肝脏中胰岛素受体底物1（IRS 1）的酪氨酸磷酸化、IRS 2的产生和Akt的磷酸化均受到抑制，而PA 28 γ（-/-）CoreTg小鼠肝脏中的这些功能均得到恢复。此外，在人肝细胞系或小鼠中，HCV核心蛋白对肿瘤坏死因子α启动子的激活被PA 28 γ基因的敲低或敲除所抑制。这些结果表明HCV核心蛋白通过PA 28 γ依赖性途径抑制胰岛素信号传导。
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.