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

Abstract

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.

Serum Galectin-3 in Hepatitis C Virus Infection Declines after Successful Virus Eradication by Direct-Acting Antiviral Therapy

“…Hepatitis C virus genotypes 1 and 3 were the most common genotypes in the current HCV patients in accordance with their global prevalence [47]. Liver steatosis is more frequent in genotype 3 than genotype 1 infected patients [48,49], whereas the frequency of diabetes is similar [50]. Serum galectin-3 did not differ between patients infected with different viral genotypes.…”

HCV Infection and Liver Cirrhosis Are Associated with a Less-Favorable Serum Cholesteryl Ester Profile Which Improves through the Successful Treatment of HCV

“…The present analysis revealed lower levels of CE 18:2 in genotype 3- than 1b-infected patients, and currently, there is no explanation for these divergent results. The two studies agree that the genotype-related changes of the CE lipidome are not apparent in patients who achieved SVR [ 53 ].…”

“…These differences did not persist at therapy end, showing that genotype 3 differently affects CE composition in comparison to genotype 1. Genotype 3-infected patients were described to have lower serum LDL cholesterol than genotype 1-infected patients [ 53 ]. Yet, CEs such as cholesteryl linoleate were higher in genotype 3 than genotype 1 [ 53 ].…”

“…Genotype 3-infected patients were described to have lower serum LDL cholesterol than genotype 1-infected patients [ 53 ]. Yet, CEs such as cholesteryl linoleate were higher in genotype 3 than genotype 1 [ 53 ]. The present analysis revealed lower levels of CE 18:2 in genotype 3- than 1b-infected patients, and currently, there is no explanation for these divergent results.…”

An Update on the Metabolic Landscape of Oncogenic Viruses

“…Similar to HBV infection, chronic HCV infection is associated with oxidative stress and inflammation, which triggers fibrosis and leads to carcinogenesis on the long term [ 227 ]. Moreover, chronic HCV infection is generally associated with metabolic disorders such as insulin resistance and steatosis [ 254 , 255 ]. HCV-induced steatosis is associated with increased risk of hepatocellular carcinoma, particularly in the context of genotype 3 [ 256 ].…”