Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Clark, Paul J., Thompson, Alexander J., Vock, David M., Kratz, Lisa E., Tolun, Adviye A., Muir, Andrew J., Mchutchison, John G., Subramanian, Mani, Millington, David M., Kelley, Richard I. and Patel, Keyur (2012) Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology, 56 1: 49-56. doi:10.1002/hep.25631

Author Clark, Paul J.
Thompson, Alexander J.
Vock, David M.
Kratz, Lisa E.
Tolun, Adviye A.
Muir, Andrew J.
Mchutchison, John G.
Subramanian, Mani
Millington, David M.
Kelley, Richard I.
Patel, Keyur
Title Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner
Journal name Hepatology   Check publisher's open access policy
ISSN 0270-9139
Publication date 2012
Year available 2012
Sub-type Article (original research)
DOI 10.1002/hep.25631
Open Access Status
Volume 56
Issue 1
Start page 49
End page 56
Total pages 8
Place of publication Hoboken, NJ United States
Publisher John Wiley and Sons, Inc.
Collection year 2013
Language eng
Subject 2721 Hepatology
Abstract Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P adj = 0.0015], 7DHC [Δ0.0075 mg/dL; P adj = 0.0026], lathosterol [Δ0.0430 mg/dL P adj = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Created: Thu, 17 Jul 2014, 09:21:22 EST by Anthony Yeates on behalf of School of Medicine