Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans

Abstract

Hepatitis C virus (HCV) exerts a profound influence on host lipid metabolism. It has been suggested that the synthesis of both fatty acids (FA) and cholesterol is dysregulated in HCV but this has not been directly quantified in humans. The purpose of this study was to measure lipogenesis and cholesterol synthesis using stable isotopes in patients with HCV (n 5 5) and healthy control (n 5 9) subjects recruited from the University of Alberta hospital. Blood samples were taken at fasting (0 and 24 hours) and after meals over the day to mimic typical food consumption and postprandial metabolism. Isolation of free cholesterol (FC), cholesteryl ester (CE), and triglyceride (TG) from plasma and very lowdensity lipoproteins (VLDL) was used to measure FA and cholesterol synthesis using deuterium uptake and isotope ratio mass spectrometry. FA composition was analyzed by gas chromatography. VLDL-TG levels of polyunsaturated fatty acids (PUFA), including linoleic and linolenic acid, were lower in HCV compared to control (P < 0.05 for both). Fasting hepatic lipogenesis was significantly higher in HCV (2.80 6 0.55%) compared to control (1.19 6 0.27%; P 5 0.03). Conversely, fasting whole-body synthesis of FC (HCV 1.64 6 0.28% versus control 8.78 6 1.59%) and CE (HCV 0.26 6 0.08% versus control 1.92 6 0.25%), as well as hepatic FC synthesis (HCV 1.68 6 0.26% versus control 8.12 6 0.77%) was lower in HCV (P < 0.001 for all). Conclusion: These data provide evidence that lipogenesis is elevated while cholesterol synthesis is impaired in HCV, supporting previous findings from cellular and animal models. Low PUFA levels combined with elevated lipogenesis suggests a role for dietary PUFA supplementation in HCV patients. (HEPATOLOGY 2013;57:1697-1704 H epatits C viral (HCV) infection is the leading cause of liver transplantation in the United States.1 Lipid metabolism, particularly very low-density lipoprotein (VLDL) machinery, 2 is commandeered by HCV and is tightly linked with HCV progression.3 Discovery of the precise and multiple mechanisms by which HCV interferes with lipid metabolism is still unfolding.Both fatty acids (FA) and cholesterol are implicated in HCV progression. De novo lipogenesis may contribute to HCV-induced damage by involvement in the viral replication process, and by contributing FAs to lipid storage in the liver, leading to steatosis. HCV is proposed to stimulate hepatic FA synthesis, as evidenced by up-regulation of enzymes involved in the lipogenic pathway such as sterol regulatory-element binding protein 1c and fatty acid synthase 4-6 in cellular and animal models of HCV. However, a quantitation of lipogenesis in human patients with HCV has not been performed. The role of cholesterol in HCV is also unclear. Patients with HCV frequently have low plasma cholesterol levels, 7 but cellular models suggest that HCV is associated with an elevation of enzymes regulating cholesterol synthesis and may be related to viral replication. 6

Hepatitis C Virus-Induced Degradation of Cell Death-Inducing DFFA-Like Effector B Leads to Hepatic Lipid Dysregulation

“…Similarly, we have observed LD formation being impaired in uninfected human hepatoma cells when CIDEB expression is reduced by shRNA or eliminated by gene knockout (29). Upon HCV infection, which increases lipogenesis (12,14,23), however, CIDEB depletion causes altered VLDL profiles and leads to intracellular lipid accumulation. Similarly, when cells were fed with excess lipids, suppression of CIDEB stabilized cytoplasmic LDs.…”

“…On the other hand, HCV infection profoundly disturbs lipid metabolism pathways (11). HCV patients exhibit enhanced lipogenesis (12), consistent with in vitro results showing that HCV infection upregulates genes encoding sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FASN), both important for the intracellular lipid synthesis pathway (13)(14)(15)(16). More recently, the 3= untranslated region (UTR) of HCV was shown to, upon binding of DDX3, activate IB kinase ␣ and trigger biogenesis of LDs (17).…”

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

“…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. Another study in 5 CHC patients used stable isotope mass spectrometry to assess plasma fatty acid composition, and demonstrated reduced cholesterol synthesis despite increased hepatic lipogenesis, compared to healthy controls [44]. However, sterol metabolites were not assessed.…”

FIG4 is a hepatitis C virus particle-bound protein implicated in virion morphogenesis and infectivity with cholesteryl ester modulation potential

“…Interestingly, the PTEN phosphatase influences CE levels through its protein phosphatase activity (Peyrou et al, 2013) and FIG4 may stimulate CE synthesis possibly by also acting as a protein phosphatase (Duex et al, 2006). Given the importance of CE biology in HCV pathophysiology and VLDL formation (Alvisi et al, 2011;Lambert et al, 2013), future studies aiming at identifying the molecular bases of this finding are certainly needed.…”