Published online Jan 8, 2017. doi: 10.4254/wjh.v9.i1.18
Peer-review started: June 30, 2016
First decision: August 10, 2016
Revised: September 10, 2016
Accepted: November 1, 2016
Article in press: November 2, 2016
Published online: January 8, 2017
Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.
Core tip: Chronic hepatitis C virus (HCV) infection leads to liver cirrhosis and cancer. HCV infection modulates the lipid metabolism. Phosphoinositides are minor phospholipids that are also modified by HCV infection. phosphatidylinositol (PtdIns)(3,4,5)P3 is mainly formed by phosphoinositide 3-kinase (PI3K), and can be dephosphorylated by SH2-containing inositol polyphosphate 5-phosphatase (SHIP2) to generate PtdIns(3,4)P2. In this review, we will discuss the effects of SHIP2 and PI3K on the formation of cell polarity and how their expression and activation are modulated by HCV infection, leading to the disruption of cell polarity. This pathway is also discussed in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.