Hepatitis C virus hijacks host lipid metabolism

Abstract

Hepatitis C virus (HCV) enhances its replication by modulating host cell lipid metabolism. HCV circulates in the blood in association with lipoproteins. HCV infection is associated with enhanced lipogenesis, reduced secretion, and beta-oxidation of lipids. HCV-induced imbalance in lipid homeostasis leads to steatosis. Many lipids are crucial for the virus life cycle, and inhibitors of cholesterol/fatty acid biosynthetic pathways inhibit virus replication, maturation and secretion. HCV negatively modulates the synthesis and secretion of very low-density lipoproteins (VLDL). Components involved in VLDL assembly are also required for HCV morphogenesis/secretion, suggesting that HCV co-opts the VLDL secretory pathway for its own secretion. This review highlights HCV-altered lipid metabolic events that aid the virus life cycle and ultimately promote liver disease.

Figure 1. HCV life Cycle

The viral life cycle is illustrated in steps i–vii. (i) HCV enters hepatocytes via putative receptors. (ii) pH-dependent fusion of the viral envelope and uncoating of genomic RNA occurs in endosomes, followed by (iii) IRES-mediated translation on the rough endoplasmic reticulum (ER). HCV proteins and their association in the ER are shown in the inset; next, (iv) assembly of ribonucleoprotein complexes (RNP) occurs, and (v) these RNP complexes engage in RNA synthesis to produce (+) polarity viral RNAs. RNA synthesis is believed to occur in the HCV-induced membranous structures termed ‘membranous web’. (vi) + polarity RNAs are encapsidated, and (vii) HCV maturation and release ensues. HCV virions traffic through the Golgi or bypass the Golgi network. The mechanistic details of steps ‘vi and vii’ are not fully characterized.

Figure 2. HCV induced alterations in lipid metabolism and steatosis

HCV alters cellular lipid metabolism to create a lipid rich intracellular environment to facilitate its own multiplication. HCV activates sterol regulatory element binding proteins (SREBPs), the master regulators of cholesterol/fatty acid biosynthesis. HCV core protein in the presence of proteasome activator PA28γ activates SREBP1c. HCV induces the downregulation of peroxisome proliferator-activated receptor α (PPAR-α), a transcription factor required for genes involved in β-oxidation and transport of fatty acids. HCV downregulates very-low-density lipoprotein (VLDL) particle secretion by inhibiting the activity of microsomal triglyceride transfer protein (MTP) activity. HCV core protein-induced rearrangement and aggregation of lipid droplets also interferes with VLDL assembly. Mitochondrial dysfunction and generation of reactive oxygen species (ROS) during HCV infection perturbs important cellular functions like VLDL assembly by promoting peroxidation of important enzymes and lipids. These events disturb lipid homeostasis leading to the intracellular accumulation of lipid droplets, which manifests as steatosis, the prominent pathological phenotype associated with HCV infection.

Figure 3. HCV co-opts the VLDL secretion pathway

HCV entry is mediated by putative receptors, but lipo-viral particle (LVP) entry into hepatocytes may be also mediated by low-density lipoprotein receptors (LDLr) and glycosoaminoglycans (GAGs). Virus binding and internalization is followed by translation of the HCV RNA genome. Details of HCV morphogenesis are not fully characterized. The HCV core protein binds to lipid droplets (LDs), and this interaction is essential for HCV genome replication and virion assembly (depicted in figure as blue dots bound to LDs). It is also presumed that HCV co-opts the very-low-density lipoprotein (VLDL) secretory pathway to facilitate its exit. The first step of VLDL assembly involves the co-translational lipidation of apoB by microsomal triglyceride transfer protein (MTP) generating a pre-VLDL particle. The pre-VLDL then matures into VLDL by fusing with large triglyceride rich droplets, presumed to occur in post-ER compartments or the Golgi. The newly assembled immature HCV virions probably fuse with the preVLDL particle prior to or during the second maturation step of VLDL generating LVPs that are secreted into the extra-cellular milieu via the VLDL route. We propose three different possibilities of how LVPs are assembled. (i) Pre-VLDL particles during their maturation process may incorporate the HCV envelope protein present on the ER membrane. The lipid droplet tethered to HCV nucleocapsid then fuses with these pre-VLDL particles carrying HCV envelope proteins, forming LVPs. (ii) Pre-VLDL and immature HCV virions fuse with each other in post-ER compartments. Lastly, it is possible that (iii) the nascent VLDL particles and immature HCV virions fuse with each other during their transit through the Golgi network.