Abstract
The hepatitis C virus (HCV) life cycle is closely associated with lipid metabolism. In particular, HCV assembly initiates at the surface of lipid droplets. To further understand the role of lipid droplets in HCV life cycle, we assessed the relationship between HCV and the adipose differentiation-related protein (ADRP), a lipid droplet-associated protein. Different steps of HCV life cycle were assessed in HCV-infected human Huh-7 hepatoma cells overexpressing ADRP upon transduction with a lentiviral vector. HCV infection increased ADRP mRNA and protein expression levels by 2- and 1.5-fold, respectively. The overexpression of ADRP led to an increase of (i) the surface of lipid droplets, (ii) the total cellular neutral lipid content (2.5- and 5-fold increase of triglycerides and cholesterol esters, respectively), (iii) the cellular free cholesterol level (5-fold) and (iv) the HCV particle production and infectivity (by 2- and 3.5-fold, respectively). The investigation of different steps of the HCV life cycle indicated that the ADRP overexpression, while not affecting the viral replication, promoted both virion egress and entry (~12-fold), the latter possibly via an increase of its receptor occludin. Moreover, HCV infection induces an increase of both ADRP and occludin expression. In HCV infected cells, the occludin upregulation was fully prevented by the ADRP silencing, suggesting a specific, ADRP-dependent mechanism. Finally, in HCV-infected human livers, occludin and ADRP mRNA expression levels correlated with each other. Alltogether, these findings show that HCV induces ADRP, which in turns appears to confer a favorable environment to viral spread.
Highlights
Hepatitis C virus (HCV) infection is a major causative agent of acute and chronic liver diseases infecting more than 170 million individuals worldwide
The HCV core protein localizes at the surface of lipid droplets (LDs) and the assembly of viral particles starts from this critical interaction [7]
As an increase in adipose differentiation-related protein (ADRP) had been shown in HCV infected patients [11], we first evaluated whether HCV had a similar effect in our cellular model
Summary
Hepatitis C virus (HCV) infection is a major causative agent of acute and chronic liver diseases infecting more than 170 million individuals worldwide. Lipids play an important role at several steps of the HCV life cycle including the viral entry, repliation, assembly and secretion. HCV infectious particles circulate in serum as lipoviroparticles. Their density are very heterogenous and depend on whether particles are associated with low density lipoprotein (LDL) or very low density lipoprotein (VLDL) [2]. Geranylgeranyl lipids generated during the cholesterol synthesis pathway play a crucial role in HCV life cycle, as NS5A needs to bind geranylgeranylated F-box and leucine rich repeat protein 2, in order to promote an efficient viral replication [6]. The HCV core protein localizes at the surface of lipid droplets (LDs) and the assembly of viral particles starts from this critical interaction [7]
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