title: Hepatitis C virus dysregulates glucose homeostasis by a dual mechanism involving induction of PGC1α and dephosphorylation of FoxO1.
abstract: 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.
authors: Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University of Basel, Basel, Switzerland.
authors: C
authors: C
authors: Bernsmeier
authors: D
authors: D
authors: Calabrese
authors: M H
authors: MH
authors: Heim
authors: H T F
authors: HT
authors: Duong
mesh_terms: D000818:Animals; D001706:Biopsy; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000473:pathology*; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D054648:Protein Phosphatase 2; D005952:Glucose-6-Phosphatase; D005947:Glucose
keywords: FoxO1; PGC1α; chronic hepatitis C; diabetes mellitus; insulin resistance