Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University of Basel, Basel, Switzerland.
J Viral Hepat. 2014 Jan;21(1):9-18. doi: 10.1111/jvh.12208. Epub 2013 Nov 6.
The maintenance of glucose homeostasis is a complex process in which the insulin signalling pathway plays a major role. Disruption of insulin-regulated glucose homeostasis is frequently observed in chronic hepatitis C (CHC) infection and might potentially contribute to type 2 diabetes mellitus (T2DM) development. Presently, the mechanism that links HCV infection to insulin resistance remains unclear. Previously, we have reported that HCV protein expression in HCV transgenic mice (B6HCV) leads to an overexpression of protein phosphatase 2A (PP2A) through an ER stress response. In the present work, we describe an association of FoxO1 hypophosphorylation and upregulation of both PGC-1α and G6Pase to phenotypic hyperglycaemia and insulin resistance in B6HCV mice. In vitro, we observed that PGC1α is concomitantly induced with PP2A. Moreover, we show that the enhanced PP2A expression is sufficient to inhibit insulin-induced FoxO1 phosphorylation via blockade of insulin-mediated Akt activation or/and through direct association and dephosphorylation of pS-FoxO1. Consequently, we found that the gluconeogenic gene glucose-6-phosphatase is upregulated. These observations were confirmed in liver biopsies obtained from CHC patients. In summary, our results show that HCV-mediated upregulation of PP2A catalytic subunit alters signalling pathways that control hepatic glucose homeostasis by inhibiting Akt and dephosphorylation of FoxO1.
葡萄糖稳态的维持是一个复杂的过程，其中胰岛素信号通路起着主要作用。慢性丙型肝炎（CHC）感染中经常观察到胰岛素调节的葡萄糖稳态失调，这可能有助于 2 型糖尿病（T2DM）的发展。目前，将 HCV 感染与胰岛素抵抗联系起来的机制尚不清楚。先前，我们已经报道 HCV 蛋白在 HCV 转基因小鼠（B6HCV）中的表达通过内质网应激反应导致蛋白磷酸酶 2A（PP2A）的过度表达。在本工作中，我们描述了 FoxO1 低磷酸化与 PGC-1α 和 G6Pase 的上调之间的关联，这与 B6HCV 小鼠的表型高血糖和胰岛素抵抗有关。在体外，我们观察到 PGC1α 与 PP2A 同时诱导。此外，我们表明增强的 PP2A 表达足以通过阻断胰岛素介导的 Akt 激活或通过直接关联和 pS-FoxO1 的去磷酸化来抑制胰岛素诱导的 FoxO1 磷酸化。因此，我们发现糖异生基因葡萄糖-6-磷酸酶被上调。这些观察结果在从 CHC 患者获得的肝活检中得到了证实。总之，我们的结果表明，HCV 介导的 PP2A 催化亚基的上调改变了通过抑制 Akt 和 FoxO1 的去磷酸化来控制肝葡萄糖稳态的信号通路。
