Abstract
Hepatitis C virus (HCV) infected patients often develop steatosis and the HCV core protein alone can induce this phenomenon. To gain new insights into the pathways leading to steatosis, we performed lipidomic profiling of HCV core protein expressing-Huh-7 cells and also assessed the lipid profile of purified lipid droplets isolated from HCV 3a core expressing cells. Cholesteryl esters, ceramides and glycosylceramides, but not triglycerides, increased specifically in cells expressing the steatogenic HCV 3a core protein. Accordingly, inhibitors of cholesteryl ester biosynthesis such as statins and acyl-CoA cholesterol acyl transferase inhibitors prevented the increase of cholesteryl ester production and the formation of large lipid droplets in HCV core 3a-expressing cells. Furthermore, inhibition of de novo sphingolipid biosynthesis by myriocin - but not of glycosphingolipid biosynthesis by miglustat - affected both lipid droplet size and cholesteryl ester level. The lipid profile of purified lipid droplets, isolated from HCV 3a core-expressing cells, confirmed the particular increase of cholesteryl ester. Thus, both sphingolipid and cholesteryl ester biosynthesis are affected by the steatogenic core protein of HCV genotype 3a. These results may explain the peculiar lipid profile of HCV-infected patients with steatosis.
Highlights
Hepatitis C virus (HCV) infects about 2.8% of the global population [1] and is a major cause of chronic liver disease and hepatic and extrahepatic mortality worldwide [2]
We found a strong increase in cholesteryl ester (CE) levels in cells expressing the genotype 3a core protein, which was not observed in cells expressing the core protein of genotype 2a or GFP (Fig. 1A, right panel)
Results are represented as mean ¡SEM. (C) Huh-7 cells were treated for 48 hours with lovastatin (10 mM) or with the SOAT inhibitor TMP-153 (25 nM) and CE levels were measured using the cholesterol/cholesteryl ester quantitation kit
Summary
Hepatitis C virus (HCV) infects about 2.8% of the global population [1] and is a major cause of chronic liver disease and hepatic and extrahepatic mortality worldwide [2]. HCV interferes with lipid metabolism, at several non-exclusive levels, favouring its own replication and virion production. Fatty liver is observed in up to 80% of chronic hepatitis C patients and occurs in hepatitis C at a frequency that is more than two-fold higher compared to the general population or even to patients with other viral liver diseases, such as chronic hepatitis B [3] This suggests that HCV may directly cause the appearance of large lipid droplets (LD) in hepatocytes. All HCV genotypes interfere with lipid metabolism, steatosis is more frequent and severe upon genotype 3 infection, suggesting that this viral genotype brings about additional perturbations in the cell biology of the host. We have recently demonstrated a role for the phosphatase and tensin homolog (PTEN) in the pathogenesis of steatosis caused by HCV of genotype 3 but not 1 [18]
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