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

Paul J. Clark, Alexander J. Thompson, David M. Vock, Lisa E. Kratz, Adviye A. Tolun, Andrew J. Muir, John G. McHutchison, Mani Subramanian, David M. Millington, Richard I. Kelley, Keyur Patel

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).