Abstract
HCV genes interfere with host cellular genes and play crucial role in pathogenesis. The mechanism under which HCV genes induce insulin resistance is not much clear. This study is aimed to examine the role of HCV NS5A in inducing insulin resistance by examining its affect in the phosphorylation level of AKT/PKB. In the present study, HepG2 cells were transfected with HCV NS5A and after 24 hours of transfection, protein was extracted from cells that were pre induced with insulin at three different time intervals i.e. 1hour, 2 hours and 3hours. Dot Blot analysis was performed to study the phosphorylation level of AKT. Results showed that there is clear upregulation of serine 473 phosphorylation level of AKT in NS5A transfected cells as compared with control (without NS5A). In conclusion, upregulation of serine 473 phosphorylation by NS5A of HCV genotype 3a suggests that this gene impairs the normal insulin AKT/PKB signaling pathway that leads towards insulin resistance and Type 2 diabetes mellitus. Therefore, HCV non-structural protein NS5A should be considered as promising candidate to be studied in detail for HCV induced insulin resistance and should be regarded as a therapeutically important target for the prevention of chronic liver diseases.
Highlights
Insulin signaling pathway is activated when tyrosine residues of IRS-1 are phosphoryalted that activates phosphatidylinositol 3-kinase (PI3K) which makes conversion of phosphatidylinositol 4, 5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-triphosphate (PIP3)
Full length NS5A gene was amplified by PCR using pcDNA 3.1/NS5A HCV as template
HCV NS5A genotype 3a contributes to insulin resistance by interfering with the functional state of AKT/PKB of insulin signaling pathway
Summary
Insulin signaling pathway is activated when tyrosine residues of IRS-1 are phosphoryalted that activates phosphatidylinositol 3-kinase (PI3K) which makes conversion of phosphatidylinositol 4, 5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-triphosphate (PIP3). Subsequently Akt/PKB (protein kinase B), gets serine/ threonine phosphorylation at the residues of Serine[473] and Threonine[308]. This leads to translocation of glucose transporter-4 (GLUT-4) to plasma membrane and increases glucose uptake. Previous research data explained crucial role of core protein by disrupting insulin signaling pathway through high expression of SOCS38 or up regulation of IRS-1 serine phosphorylation by c-Jun N-terminal kinase (JNK) activation[9]. This results in disruption of downstream signaling and degradation of IRS-1 function. There is an urgent need to analyze the critical role of HCV protein in developing insulin resistance and HCV induced type 2 Diabetes mellitus (T2DM)[14]
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