Hepatitis C virus NS5A protein enhances gluconeogenesis through upregulation of Akt-/JNK-PEPCK signalling pathways
Journal
Liver International
Journal Volume
34
Journal Issue
9
Pages
1358-1368
Date Issued
2014
Author(s)
Abstract
Background & Aims: Hepatitis C virus (HCV) infection is highly associated with the type 2 diabetes mellitus, but the detailed mechanisms by which the viral proteins are involved in the clinical outcome remain unclear. Methods: A cDNA microarray analysis was performed following introducing an NS5A-encoding plasmid or a control vector into a mouse system by hydrodynamics-based transfection. Differentially expressed genes that are associated with gluconeogenesis were selected and their expression levels in HCV patients, in NS5A-expressing systems, and in the viral subgenomic replicon system were further examined by real-time quantitative polymerase chain reaction and Western blot analysis. Results: Differential gene expression including an upregulation of the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) compared with controls was detected in mouse hepatocytes expressing HCV NS5A and in HCV patients with diabetes. In addition, an NS5A-dependent increase in glucose production was demonstrated in human primary hepatocytes. The upregulation of PEPCK and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were also detected in NS5A-expressing cells and in the viral genotype 1b subgenomic replicon system. Further studies demonstrated that the NS5A-mediated upregulation of PEPCK and PGC-1α genes were resulted from the activation of PI3K-Akt and JNK signalling pathways. In addition, the expression levels of the forkhead transcription factor FoxO1 and the liver-enriched transcription factor HNF-4α were increased in HCV NS5A-expressing cells. Conclusions: By upregulating the expression of PEPCK gene via its transactivators FoxO1 and HNF-4α, and the coactivator PGC-1α, the NS5A promotes the production of hepatic glucose which may contribute to the development of HCV-associated type 2 diabetes mellitus. ? 2013 John Wiley & Sons A/S.
SDGs
Other Subjects
hepatocyte nuclear factor 4alpha; nonstructural protein 5A; peroxisome proliferator activated receptor gamma coactivator 1alpha; phosphoenolpyruvate carboxylase; protein kinase B; stress activated protein kinase; transcription factor FKHR; glucose; mitogen activated protein kinase kinase 4; NS-5 protein, hepatitis C virus; oncoprotein; phosphoenolpyruvate carboxykinase (ATP); virus protein; animal cell; Article; controlled study; enzyme activation; enzyme regulation; gene expression; gluconeogenesis; Hepatitis C virus; human; human cell; mouse; non insulin dependent diabetes mellitus; nonhuman; polymerase chain reaction; signal transduction; upregulation; Western blotting; animal; complication; Diabetes Mellitus, Type 2; DNA microarray; gene expression regulation; genetic transfection; gluconeogenesis; Hepacivirus; hepatitis C; liver cell; metabolism; physiology; real time polymerase chain reaction; virology; Animals; Blotting, Western; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gluconeogenesis; Glucose; Hepacivirus; Hepatitis C; Hepatocytes; Humans; MAP Kinase Kinase 4; Mice; Oligonucleotide Array Sequence Analysis; Oncogene Protein v-akt; Phosphoenolpyruvate Carboxykinase (ATP); Real-Time Polymerase Chain Reaction; Signal Transduction; Transfection; Viral Nonstructural Proteins
Publisher
Blackwell Publishing Ltd
Type
journal article