Hepatitis C Virus Proteins Induce Lipogenesis and Defective Triglyceride Secretion in Transgenic Mice

Abstract

Chronic hepatitis C virus (HCV) infection is associated with altered lipid metabolism and hepatocellular steatosis. Virusinduced steatosis is a cytopathic effect of HCV replication. The goal of this study was to examine the mechanisms underlying HCV-induced lipid metabolic defects in a transgenic mouse model expressing the full HCV protein repertoire at levels corresponding to the human infection. In this model, expression of the HCV full-length open reading frame was associated with hepatocellular steatosis and reduced plasma triglyceride levels. Triglyceride secretion was impaired while lipogenesis was activated. Increased lipogenic enzyme transcription resulted from activation at the maturation step and nuclear translocation of sterol regulatory element binding protein 1c (SREBP1c). No ER-stress marker was expressed at significantly higher levels in HCV transgenic mice than in their wild-type counterparts, suggesting that SREBP1c proteolytic cleavage was independent of ER stress. In conclusion, transgenic mice expressing the HCV full-length polyprotein at low, physiological levels, have decreased plasma triglyceride levels and develop hepatocellular steatosis in the same way as HCV-infected patients. In these mice, de novo triglyceride synthesis is induced by direct SREBP1c activation by one or several HCV proteins through induction of the lipogenic pathway, independently of ER stress, while triglyceride secretion is simultaneously reduced.

Increased Phosphoenolpyruvate Carboxykinase Gene Expression and Steatosis during Hepatitis C Virus Subgenome Replication

“…Unlike gluconeogenesis, the relative roles of various factors in the accumulation of lipid are difficult to estimate, but the net result was steatotic hepatocytes. HCV is known to inhibit lipoprotein export while increasing lipid uptake and VLDL biosynthesis (39). Currently, it is believed that HCV co-opts the VLDL assembly, maturation, degradation, and secretory machinery of the hepatocyte (reviewed in Ref.…”

“…Comparison of Lipogenic Gene Expression in Huh7 and Huh.8 Cells with C/EBP␤ Knockdown-Liver TG accumulation and inflammation are pivotal metabolic hallmarks in the natural history of HCV infection, which are at least in part controlled by peroxisome proliferator-activated receptors (PPARs) and the key transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) (39). We previously showed that C/EBP␤ deletion prevented fatty liver and down-regulated genes that regulate hepatic lipogenesis and TG metabolism in genetically obese db/db mice and in a dietary-induced fatty liver model (17,18).…”

Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent

“…In this model, the HCV proteins are expressed within hepatocytes at levels close to those observed in human infection, without infectious virus production or an antiviral immune response. These mice develop lesions similar to those observed during natural infection, including hepatic steatosis and hepatocellular carcinoma [2][3][4][5][6].…”

Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR- in Huh-7 cells

“…It has been shown that growing cells in delipidated medium reduce the triglyceride accumulation induced by HCV core protein genotype 3a, suggesting a lack of de novo synthesis of triglycerides (Abid et al, 2005) and suggesting that the core protein seems to promote a mere redistribution of fat-laden vesicles typically found in Huh-7 cells, rather than a true triglyceride accumulation. On the other hand, the core protein alone is able to modulate the expression of several cellular genes involved in lipid metabolism (Pazienza et al, 2009) and/or to promote de novo triglyceride synthesis (Lerat et al, 2009). …”