Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis

Sheridan, David A., Shawa, Isaac Thom, Thomas, E. Louise, Felmlee, Daniel J., Bridge, Simon, Neely, Dermot, Cobbold, Jeremy F., Holmes, Elaine, Bassendine, Margaret F. and Taylor-Robinson, Simon D. (2022) Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis. Scientific Reports, 12 (1). p. 5562. ISSN 2045-2322

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Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.

Item Type: Article
Additional Information: Funding Information: This work was funded by the Medical Research Council UK, (Grant Number G0502028) to Margaret F Bassendine as Principal Investigator; and by the Wellcome Trust ISSF Fund at Imperial College London. Jeremy Cobbold was funded by the Hammersmith Hospital Centenary PhD program at Imperial College London. Running costs were also provided by a generous donation from the friends and family of Mr and Mrs Barry Winter and of Mrs Suzy Dunn.
Subjects: B900 Others in Subjects allied to Medicine
C500 Microbiology
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: John Coen
Date Deposited: 19 Apr 2022 12:11
Last Modified: 19 Apr 2022 12:15

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