Hepatic steatosis is common in patients infected with hepatitis C virus (HCV). Particularly in patients infected with non-genotype 3 HCV, hepatic steatosis is closely related to factors of the
metabolic syndrome such as
hyperlipidemia. However, the molecular mechanisms involved in this "metabolic" steatosis in non-3 genotype HCV
infections are not well understood. Here, we aimed to develop an in vitro model to study the effect of genotype 1 HCV
infection on hepatic lipotoxicity and lipid metabolism. Cellular
lipid accumulation was induced in Huh-7
hepatoma cells transfected with HCV genotype 1b replicon (HCV+) by incubation with increasing doses of
palmitic acid (C16:0) or
oleic acid (C18:1 n-9) complexed to
albumin mimicking hyperlipidemic conditions. Mock transfected
hepatoma cells (HCV-) were used as controls. Incubation with
oleic acid concentrations as high as 0.5 mM did not induce toxic effects in HCV+ or HCV- cells. In contrast, incubation with
palmitic acid caused dose-dependently cytotoxic effects which were more pronounced in HCV+ compared to HCV- cells. Further analysis with subtoxic palmitic and
oleic acid concentrations revealed a higher uptake of
fatty acids and intracellular
triglyceride accumulation in HCV+ compared to HCV- cells.
Carnitine palmitoyltransferase I (CPT1) expression, indicative of mitochondrial beta-oxidation, was markedly stimulated by
lipid exposure in HCV+ but not in HCV- cells. Furthermore,
heme oxygenase 1 (HMOX1) expression levels increased in FA stimulated cells, and this increase was significantly higher in HCV+ compared to HCV- cells. In contrast, expression of the key
enzymes of hepatic de novo lipogenesis
fatty acid synthase (FASN) and
stearoyl-CoA desaturase (SCD-1) was significantly reduced upon
oleate exposure in HCV- but not in HCV+ cells. In summary, our newly developed cell culture model revealed effects of HCV genotype 1b
infection on metabolic susceptibility to
lipid accumulation and toxicity particularly to saturated
lipids. These results may indicate that HCV (genotype 1b) infected individuals with
hyperlipidemia may benefit from dietary or pharmacological intervention.