Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3β signaling in hepatocytes

School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan. .
BMC Gastroenterology (Impact Factor: 2.37). 06/2012; 12(1):74. DOI: 10.1186/1471-230X-12-74
Source: PubMed


Hepatitis C virus (HCV) infection may cause liver diseases of various severities ranging from primary acute infection to life-threatening diseases, such as cirrhosis or hepatocellular carcinoma with poor prognosis. According to clinical findings, HCV infection may also lead to some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Since insulin resistance is the major etiology for type 2 DM and numerous evidences showed that HCV infection associated with insulin resistance, the involvement of E2 in the pathogenesis of type 2 DM and underlying mechanisms were investigated in this study.
Reverse transcription and real-time PCR, Western blot assay, Immunoprecipitation, Glucose uptake assay and analysis of cellular glycogen content.
Results showed that E2 influenced on protein levels of insulin receptor substrate-1 (IRS-1) and impaired insulin-induced Ser308 phosphorylation of Akt/PKB and Ser9 phosphorylation of GSK3β in Huh7 cells, leading to an inhibition of glucose uptake and glycogen synthesis, respectively, and eventually insulin resistance.
Therefore, HCV E2 protein indeed involved in the pathogenesis of type 2 DM by inducing insulin resistance.

Download full-text


Available from: Ming-Ju Hsieh, Apr 08, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.
    No preview · Article · Aug 2012 · Journal of Agricultural and Food Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Hepatitis C virus (HCV) causes acute and chronic human hepatitis infection and as such is an important global health problem. The virus was discovered in the USA in 1989 and it is now known that three to four million people are infected every year, WHO estimating that 3 percent of the 7 billion people worldwide being chronically infected. Humans are the natural hosts of HCV and this virus can eventually lead to permanent liver damage and carcinoma. HCV is a member of the Flaviviridae family and Hepacivirus genus. The diameter of the virus is about 50-60 nm and the virion contains a single-stranded positive RNA approximately 10,000 nucleotides in length and consisting of one ORF which is encapsulated by an external lipid envelope and icosahedral capsid. HCV is a heterogeneous virus, classified into 6 genotypes and more than 50 subtypes. Because of the genome variability, nucleotide sequences of genotypes differ by approximately 31-34%, and by 20-23% among subtypes. Quasi-species of mixed virus populations provide a survival advantage for the virus to create multiple variant genomes and a high rate of generation of variants to allow rapid selection of mutants for new environmental conditions. Direct contact with infected blood and blood products, sexual relationships and availability of injectable drugs have had remarkable effects on HCV epidemiology. Hundreds of thousands of people die each year from hepatitis and liver cancer caused by HCV virus infection. Approximately 80% of patients with acute hepatitis C progress into a chronic disease state leading to serious hepatic disorders, 10-20% of which develop chronic liver cirrhosis and hepatocellular carcinoma. The incubation period of HCV is 6-8 weeks and the infection is often asymptomatic so it is very hard to detect at early stages, making early treatment very difficult. Therefore, hepatitis C is called a "silent disease". Neutralizing antibodies are produced against several HCV proteins during infection but the virus mutates to escape from antibodies. Some patients with chronic hepatitis C may have some symptoms such as fatigue, muscle aches, nausea and pain. Autoimmune and immunecomplex-mediated diseases have also been reported with chronic HCV infection.
    No preview · Article · Dec 2012 · Asian Pacific journal of cancer prevention: APJCP
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection is highly prevalent worldwide and most of HCV infections enter into chronic phase subsequently leading to insulin resistance (IR) and clinical complications. Although the clinics of chronic HCV infection is well described, there is need to better understand the molecular mechanisms of HCV-induced IR. Therefore this study was aimed to unveil the role of host genes involved in the development of HCV-induced IR. For this purpose the expression of selected genes in HCV-infected and non-infected Huh-7 cells at various time post infection (p.i.) was assayed by real-time PCR. HCV infection was found to trigger endoplasmic reticulum (ER) stress response as demonstrated by an increase in the expression of calreticulin (Cal) gene but no change in the expression of Gadd153 gene. The infection also enhanced the expression of suppressor of cytokine signaling 3 (SOCS-3), responsible for the degradation of insulin receptor substrates (IRS). Moreover, it led to a decreased expression of key signaling molecules IRS-1 and IRS-2, unchanged expression of SOCS-7 and increased expression of downstream signaling molecule Akt. Altogether these findings indicate that the HCV infection induces ER stress and IR in Huh-7 cells in vitro.
    Full-text · Article · Sep 2014 · Acta Virologica
Show more