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Updated: Sep 28, 2025
Lipid Droplet Isolation for Quantitative Mass Spectrometry Analysis
Published on: April 17, 2017
Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic
David A Sheridan1, Isaac Thom Shawa2,3, E Louise Thomas4
1Hepatology Research Group, Faculty of Health, University of Plymouth, Plymouth, PL6 8BU, UK. david.sheridan@plymouth.ac.uk.
Insights
Hepatitis C virus genotype 3 (HCV-G3) infection is linked to lower LDL cholesterol and increased hepatic steatosis compared to HCV genotype 1 (HCV-G1). These lipid metabolism differences may influence liver disease progression and cancer risk.
Area of Science:
- Hepatology and Viral Gastroenterology
- Metabolomics and Lipidomics
- Molecular and Cellular Biology
Background:
- Chronic hepatitis C virus (HCV) infection alters host lipid metabolism, with implications for liver disease progression and hepatocellular carcinoma (HCC) risk.
- Hepatocellular carcinoma (HCC) risk is proposed to be independently associated with HCV genotype 3 (HCV-G3) infection, potentially involving lipogenic proteins.
- Understanding genotype-specific lipid alterations is crucial for elucidating differential disease trajectories in HCV infection.
Purpose of the Study:
- To characterize and compare host lipid metabolism variations between patients chronically infected with HCV genotype 1 (HCV-G1) and HCV genotype 3 (HCV-G3).
- To identify genotype-specific differences in lipid metabolism that may contribute to varying liver disease progression and HCC risk.
Main Methods:
- Multi-platform lipidomic analysis of serum samples from 112 HCV-G1 and HCV-G3 infected patients (fasting state) and a comparative cohort (non-fasting).
- Measurement of serum lipids using enzymatic assays, lathosterol and desmosterol via gas-chromatography mass spectrometry (GC-MS).
- Ultra-performance liquid chromatography mass spectrometry (UPLC-MS) for in-depth metabolic profiling and in vivo magnetic resonance imaging (MRI) for body fat distribution in a subgroup.
Main Results:
- HCV-G3 patients exhibited significantly lower serum apoB and non-HDL cholesterol, and increased hepatic steatosis compared to HCV-G1 patients.
- Significantly decreased serum lathosterol levels were observed in HCV-G3 patients, indicating suppressed cholesterol synthesis, without significant changes in desmosterol.
- Lipidomic profiling revealed alterations in the reverse cholesterol transport pathway in HCV-G3, characterized by low LDL cholesterol and preferential suppression of cholesterol synthesis.
Conclusions:
- HCV-G3 infection is distinctly characterized by low LDL cholesterol and suppressed cholesterol synthesis (via lathosterol), coupled with increased hepatic steatosis, compared to HCV-G1.
- These genotype-specific lipid disturbances provide insights into the differential progression of liver disease and the promotion of hepatocellular carcinoma in HCV-G3.
- Targeting lipid metabolism pathways may offer novel therapeutic strategies for managing HCV-associated liver disease and reducing HCC risk.
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.
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