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Review
, 5 (5), 1292-324

Hepatitis C Virus, Cholesterol and Lipoproteins--Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

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Review

Hepatitis C Virus, Cholesterol and Lipoproteins--Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

Daniel J Felmlee et al. Viruses.

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.

Figures

Figure 1
Figure 1
Functional comparison between cytosolic lipid droplets, very-low density lipoprotein (VLDL), and lipoviral particles (LVP). (A) Hepatic cytosolic lipid droplets (LD) and (B) VLDL share common properties and functions albeit in different compartments. The lipid components of both LDs and VLDL particles consists of a hydrophobic triglyceride and cholesteryl-ester core surrounded by a free cholesterol and phospholipid monolayer where amphipathic proteins may be embedded or peripherally associated, including adipose differentiation-related protein (ADRP/PLIN2) and Tail interacting Protein of 47 kDa (TIP47/PLIN3) for LDs [18,19], and apolipoproteins (apos) including apoB, apoE, apoCI-III for VLDL [20]. The functions of these proteins are analogous: to stabilize assembly, to provide docking sites for the appropriate receptors and regulatory proteins, and to regulate access to underlying lipids [21]. (C) Hepatitis C virus (HCV) particles in patient sera circulate in complexes with host lipoproteins as lipoviral particles, which are enriched in triglyceride, cholesterol, and several apolipoproteins [22,23].
Figure 2
Figure 2
HCV hepatocyte entry. HCV entry into human hepatocytes is a multi-step process in which many host factors are involved including heparan sulfate proteoglycans (HSPGs), the low density lipoprotein receptor (LDLr), the scavenger receptor class B type I (SR-BI), tetraspanin CD81, the tight junction proteins, claudin-1 (CLDN1) and occludin (OCLN), receptor tyrosine kinases (RTKs),and the Niemann–Pick C1-like 1 (NPC1L1) (reviewed in [131]). The LVP initially binds HSPGs and LDLR via apoE. Subsequent interaction with SR-BI, CD81, CLDN1, and OCLN leads to viral internalization in cholesterol-rich microdomains via clathrin-mediated endocytosis. Other entry factors such as RTKs and NPC1L1 are regulatory cofactors. RTKs promote viral entry by signal transduction inducing CD81–CLDN1 associationand membrane fusion [132,133] while NPC1L1 likely acts on cholesterol regulation. The factors involved in lipid and lipoprotein metabolism that relate to HCV entry step are listed in the red box including lipoprotein lipase (LpL), hepatic lipase (HL), and apolipoproteins E, B, CI, and AI (apoE, apoB, apoCI, apoAI).
Figure 3
Figure 3
Interactions between HCV and lipid regulating factors during HCV replication and assembly. In conjunction with PI4K-IIIα (Phosphatidylinositol 4-kinase III α), viral proteins induce rearrangement of endoplasmic reticulum (ER)-derived membranes forming HCV replication complexes in modified “membranous webs” (MW) in association with cytosolic lipid droplets (cLD) [182]. Virion assembly occurs on core-enriched LDs, loaded with triglyceride by diacylglycerol acyltransferase-1 (DGAT1) [183]. LD protein Tail interacting Protein of 47 kDa (TIP47) binds RNA associated NS5A in replication complexes and mobilizes it to these LDs [184]. ApoE binds NS5A, effecting early stages of HCV assembly [119]. Packaging of the capsid occurs by viral budding into the ER lumen at sites of VLDL synthesis. VLDL synthesis is mediated by microsomal triglyceride transfer protein (MTP), which lipidates apoB and luminal ApoE-bound LDs (LuLDs) that fuse and mature to form VLDL [21]. Host factors involved in lipid metabolism and HCV replication, assembly, and production include those listed in the red box: micro-RNA 122 (miR-122), sphingomyelin synthases 1 and 2 (SMS1 & 2), F-box and leucine-rich repeat protein 2 (FBL2), subtilisin/kexin-isozyme-1 or site-1 protease (SK-I/S1P), ceramide transfer protein (CERT), oxysterol binding protein (OSBP), apolipoprotein A1 (apoA1).

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