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

Publication ,  Journal Article
Clark, PJ; Thompson, AJ; Vock, DM; Kratz, LE; Tolun, AA; Muir, AJ; McHutchison, JG; Subramanian, M; Millington, DM; Kelley, RI; Patel, K
Published in: Hepatology
July 2012

UNLABELLED: 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.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

July 2012

Volume

56

Issue

1

Start / End Page

49 / 56

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Statistics, Nonparametric
  • Signal Transduction
  • Severity of Illness Index
  • Risk Assessment
  • Ribavirin
  • Prognosis
  • Pilot Projects
  • Oxidative Stress
  • Middle Aged
 

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Clark, P. J., Thompson, A. J., Vock, D. M., Kratz, L. E., Tolun, A. A., Muir, A. J., … Patel, K. (2012). Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology, 56(1), 49–56. https://doi.org/10.1002/hep.25631
Clark, Paul J., Alexander J. Thompson, David M. Vock, Lisa E. Kratz, Adviye A. Tolun, Andrew J. Muir, John G. McHutchison, et al. “Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner.Hepatology 56, no. 1 (July 2012): 49–56. https://doi.org/10.1002/hep.25631.
Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology. 2012 Jul;56(1):49–56.
Clark, Paul J., et al. “Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner.Hepatology, vol. 56, no. 1, July 2012, pp. 49–56. Pubmed, doi:10.1002/hep.25631.
Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, McHutchison JG, Subramanian M, Millington DM, Kelley RI, Patel K. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology. 2012 Jul;56(1):49–56.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

July 2012

Volume

56

Issue

1

Start / End Page

49 / 56

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Statistics, Nonparametric
  • Signal Transduction
  • Severity of Illness Index
  • Risk Assessment
  • Ribavirin
  • Prognosis
  • Pilot Projects
  • Oxidative Stress
  • Middle Aged