Steatosis and insulin resistance in hepatitis C: a way out for the virus?
The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas metabolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expression and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor gamma (PPARgamma), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an efficient mechanism for stable viral replication. Chronic HCV infection can also induce insulin resistance. In patients with HCV, insulin resistance is more strongly associated with viral load than visceral obesity. HCV seems to lead to insulin resistance through interference of intracellular insulin signalling by HCV proteins, mainly, the serine phosphorylation of insulin receptor-1 (IRS-1) and impairment of the downstream Akt signalling pathway. The HCV core protein interferes with in vitro insulin signalling by genotype-specific mechanisms, where the role of suppressor of cytokine signal 7 (SOCS-7) in genotype 3a and mammalian target of rapamycin (mTOR) in genotype 1 in IRS-1 downregulation play key roles. Steatosis and insulin resistance have been associated with fibrosis progression and a reduced rate of sustained response to peginterferon plus ribavirin.
Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Ctra de Cadiz s/n, Sevilla 41014, Spain.
José A
JA
Del Campo
Manuel
M
Romero-Gómez
D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications*; D005355:Fibrosis / Q000473:pathology; D005838:Genotype; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007333:Insulin Resistance; D008055:Lipids / Q000737:chemistry; D024821:Metabolic Syndrome / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D008055:Lipids; D009687:Nuclear Proteins; D047495:PPAR gamma; C108775:SOCS7 protein, human; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D050826:Suppressor of Cytokine Signaling Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases