Molecular mechanism of hepatitis C virus-induced glucose metabolic disorders

Abstract

Hepatitis C virus (HCV) infection causes not only intrahepatic diseases but also extrahepatic manifestations, including metabolic disorders. Chronic HCV infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Glucose is transported into hepatocytes via glucose transporter 2 (GLUT2). Hepatocytes play a crucial role in maintaining plasma glucose homeostasis via the gluconeogenic and glycolytic pathways. We have been investigating the molecular mechanism of HCV-related type 2 diabetes using HCV RNA replicon cells and HCV J6/JFH1 system. We found that HCV replication down-regulates cell surface expression of GLUT2 at the transcriptional level. We also found that HCV infection promotes hepatic gluconeogenesis in HCV J6/JFH1-infected Huh-7.5 cells. HCV infection transcriptionally up-regulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. Gene expression of PEPCK and G6Pase was regulated by the transcription factor forkhead box O1 (FoxO1) in HCV-infected cells. Phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells, resulting in increased nuclear accumulation of FoxO1. HCV NS5A protein was directly linked with the FoxO1-dependent increased gluconeogenesis. This paper will discuss the current model of HCV-induced glucose metabolic disorders.

Keywords: FoxO1; GLUT2; HCV; JNK; NS5A; diabetes; gluconeogenesis.

Figure 1

Regulation of Gluconeogenesis and Glycolysis in the HCV-infected cells. HCV infection promotes gluconeogenesis via transcriptional up-regulation of the genes for PEPCK and G6Pase, the rate-limiting enzymes for hepatic gluconeogenesis, and transcriptional down-regulation of the gene for GK, the rate-limiting enzyme for hepatic glycolysis.

Figure 2

A proposed mechanism of HCV-induced glucose metabolic disorders. HCV infection down-regulates cell surface expression of GLUT2 in hepatocytes at the transcriptional level. HCV down-regulates a transcription factor involved in GLUT2 gene expression through an unknown mechanism. HCV infection induces mitochondria damage and ROS production, leading to JNK activation. HCV NS4A protein is involved in mitochondrial damage. HCV NS5A protein is involved in ROS production. HCV-induced ROS production causes JNK activation, resulting in the decreased phosphorylation and nuclear accumulation of FoxO1. Nuclear accumulation of FoxO1 up-regulates gene expression of PEPCK and G6Pase, leading eventually to increased glucose production by gluconeogenesis. High glucose levels in the hepatocytes may confer an advantage in efficient replication of HCV.