Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets

Abstract

Hepatitis C virus (HCV) perturbs the host's lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV-induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down-regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down-regulated PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN messenger RNA translation. PTEN down-regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down-regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN-dependent mechanisms are involved in this process. Conclusion: The down-regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a-induced formation of large lipid droplets in hepatocytes. (HEPATOLOGY 2011;54:38-49)

HCV genotype 3: a wolf in sheep’s clothing

“…[15] Secondly, another problem that is not well understood is the interaction between HCV and lipid metabolism. [16] So, HCV G3 selectively interferes with the late cholesterol synthesis pathway, [17] although this interference is resolved after the SVR. Other mechanisms that alter lipid metabolism are increased the novo lipogenesis and the inhibition of mitochondrial fatty acid degradation.…”

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

“…Regarding the liver, we previously reported that PTEN is downregulated in steatotic livers of obese patients, as well as in rat models of genetic or diet-induced obesity [13]. Likewise, PTEN is downregulated in the liver of patients infected with hepatitis C virus (HCV) [14]. Interestingly, both obesity and HCV infection are associated with the development of steatosis and IR.…”

Hepatitis C Virus Core Protein Decreases Lipid Droplet Turnover

“…In support of a model where core plays a direct role in altering transcriptional events, core was shown to bind and activate the DNA-binding domain of the retinoid X receptor ␣, a transcriptional regulator involved in the regulation of cellular lipid synthesis (24). It was recently shown that genotype 3a core protein induces the formation of large lipid droplets in hepatoma cells by decreasing the expression of phosphatase and tensin homolog and insulin receptor substrate 1 (IRS-1) (25). IRS-1 has also been linked to the development of insulin resistance in HCV-infected patients in a genotype-specific manner; genotype 3a core causes IRS-1 degradation through down-regulation of peroxisome proliferator-activated receptor ␥ and up-regulation of suppressor of cytokine signal 7 (SOCS7), whereas genotype 1b core instead activates the mammalian target of rapamycin (mTOR) pathway (26).…”