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Chronic Hepatitis C virus has the potential of inducing insulin resistance and type 2 Diabetes Mellitus in vitro as well as in vivo . Structural and non-structural proteins of HCV modulate cellular gene expression in such a way that insulin signaling is hampered, concomitantly leads toward diabetes mellitus. A number of mechanisms have been proposed in regard to the HCV induced insulin resistance involving the upregulation of Inflammatory cytokine TNF-α, hypophosphorylation of IRS-1 and IRS-2, phosphorylation of Akt, up-regulation of gluconeogenic genes, accumulation of lipids and targeting lipid storage organelles. This review provides an insight of molecular mechanisms by which HCV structural and non-structural proteins can induce insulin resistance.

Taken together, our results suggest the role of HCV NS5A in the induction of insulin resistance by modulating various cellular targets involved in the insulin signaling pathway.

Purinergic P2X receptors are plasma membrane bound, ATP-gated ion channels that are expressed on wide range of cells and respond to varying ATP concentrations in extracellular environment. Upon activation they increase membrane permeability for Ca(2+) ions and trigger a cascade of signaling complexes. During the course of hepatitis C virus (HCV) infection, ATP is released from the infected hepatocyte, which binds with Purinergic receptors (P2X) on peripheral blood mononuclear cells (PBMCs) and initiate downstream signaling pathways by disturbing the ionic balance of the cell. The present study investigates quantitative expression of P2X7 and P2X4 along with selected host genes PEPCK, transforming growth factor β (TGF-β), MAPK, Rho, and Akt in PBMCs of chronic HCV infection patients. PBMCs were isolated from collected blood samples of study subjects. Transcript analysis of P2X7, P2X4, and targeted downstream genes was done using quantitative real-time polymerase chain reaction. Relative expression analysis was performed by unpaired Student's t test on GraphPad Prism version 5. We found a notable increase of threefolds and 1.8-folds in the expression of P2X7 and P2X4 receptors in treatment naïve category while the expression of PEPCK, TGF-β, MAPK, AKT, and Rho A increased by 2.8, 1.9, 2.2, 2.2, and 1.8-folds, respectively. In sustained virological response patients, P2X7 significantly increased up to 3.5-folds while the expression of P2X4 receptor was increased up to twofold. In third category, treatment nonresponder, the expression of P2X7, P2X4 receptors, and targeted markers remained un-altered. This study deals with two major aspects of P2X4 and P2X7 receptors in PBMCs of chronic HCV individuals. One is their role in providing antiviral immunity to host against HCV; second aspect is the role of P2X receptors in inducing HCV pathogenesis via AKT, TGF-β, Rho A, PEPCK, and MAPK expression.

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Hepatitis C virus (HCV) infection is the most important problem across the world. It causes acute and chronic liver infection. Different approaches are in use to inhibit HCV infection, including small organic compounds, siRNA, shRNA and peptide inhibitors. This review article summarizes the current and future therapies for HCV infection. PubMed and Google Scholar were searched for articles published in English to give an insight into the current inhibitors against this life-threatening virus. HCV NS3/4A protease inhibitors and nucleoside/nucleotide inhibitors of NS5B polymerase are presently in the most progressive stage of clinical development, but they are linked with the development of resistance and viral breakthrough. Boceprevir and telaprevir are the two most important protease inhibitors that have been approved recently for the treatment of HCV infection. These two drugs are now the part of standard-of-care treatment (SOC). There are also many other drugs in phase III of clinical development. When exploring the various host-cell-targeting compounds, the most hopeful results have been demonstrated by cyclophilin inhibitors. The current SOC treatment of HCV infection is Peg-interferon, ribavirin and protease inhibitors (boceprevir or telaprevir). The future treatment of this life-threatening disease must involve combinations of therapies hitting multiple targets of HCV and host factors. It is strongly expected that the near future, treatment of HCV infection will be a combination of direct-acting agents (DAA) without the involvement of interferon to eliminate its side effects.

Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.