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

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 5 13) and G3 (n 5 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 5 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj 5 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [D55.2 mg/dL; P adj 5 0.0015], 7DHC [D0.0075 mg/dL; P adj 5 0.0026], lathosterol [D0.0430 mg/dL P adj 5 0.0405]). In contrast, lanosterol was unchanged after SVR (P 5 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. (HEPATOLOGY 2012;56:49-56)

Vitamin D Receptor FokI Gene Polymorphism Predicted Poor Response to Treatment in Chronic HCV Genotype 4

“…[28,29] All our HCV-4 patients had suboptimal vitamin D levels with the majority being severely deficient (86%). Possible explanations for the association of HCV with vitamin D deficiency have included decreased 25-alpha hydroxylation in the liver, HCV may have the ability to directly suppress 25-alpha hydroxylation through inducing cytokines and oxidative stresses, and a recent study has shown that HCV alters lipid metabolism directly reducing production of 7-dehydrocholesterol, the precursor of endogenouslyproduced vitamin D. [30,31] The independent effect of HCV on vitamin D levels is strongly supported by our finding of the remarkable improvement in vitamin D levels after successful eradication of HCV and its persistence in non-responders. Further studies are definitely recommended to depict the exact mechanisms by which HCV alters vitamin D production and metabolism.…”

HCV genotype 3: a wolf in sheep’s clothing

“…[15] Secondly, another problem that is not well understood is the interaction between HCV and lipid metabolism. [16] So, HCV G3 selectively interferes with the late cholesterol synthesis pathway, [17] although this interference is resolved after the SVR. Other mechanisms that alter lipid metabolism are increased the novo lipogenesis and the inhibition of mitochondrial fatty acid degradation.…”

Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin

“…Our study indicated that the distal post-squalene sterol metabolites lathosterol, desmosterol and 7-DHC were lower in GT3 patients compared to GT2. A prior small study in 33 CHC patients (GT2=13, GT3=20) treated with IFN-based therapy indicated no baseline genotype differences in distal sterol metabolites, except for 7-DHC [21].In contrast, our study included a larger cohort with both fibrosis assessment and sterol metabolite measurement at end-of-treatment, to allow for clinically relevant subgroup analyses in relation to genotype, relapse, and advanced disease. In addition, our study also demonstrated on-treatment increases in desmosterol and lanosterol for GT3 patients, and a novel independent association between baseline lathosterol and SVR.…”

“…A small pilot study demonstrated HCV GT3-specific perturbation of distal cholesterol biosynthesis metabolites but the preservation of proximal metabolites such as lanosterol [21]. However, the pathogenic mechanisms and reasons for this genotype-specific inhibition of cholesterol biosynthesis pathway to provide a survival advantage to the virus are poorly understood.…”