Adiponectin serum level in chronic hepatitis C infection and therapeutic profile

Abstract

Hepatic steatosis is commonly seen in the patients with chronic hepatitis C virus (HCV) infection. HCV is closely associated with lipid metabolism, and viral steatosis is more common in genotype 3 infection owing to a direct cytopathic effect of HCV core protein. In non-genotype 3 infection, hepatic steatosis is considered largely to be the result of the alterations in host metabolism; metabolic steatosis is primarily linked with HCV genotype 1. Adipose tissue secretes different hormones involved in glucose and lipid metabolisms. It has been demonstrated that adipocytokines are involved in the pathogenesis of non-alcoholic fatty liver disease, as the decreased plasma adiponectin levels, a soluble matrix protein expressed by adipoctyes and hepatocyte, are associated with liver steatosis. Various studies have shown that steatosis is strongly correlated negatively with adiponectin in the patients with HCV infection. The role of adiponectin in hepatitis C virus induced steatosis is still not completely understood, but the relationship between adiponectin low levels and liver steatosis is probably due to the ability of adiponectin to protect hepatocytes from triglyceride accumulation by increasing β-oxidation of free fatty acid and thus decreasing de novo free fatty acid production.

Keywords: Adiponectin; Hepatitis C virus; Hepatitis C virus core protein; Insulin resistance; Metabolism.

Figure 1

Molecular pathways involved in anti-steatotic effect of adiponectin. The interaction between adiponectin receptor and APPL1 causes activation of AMPK. AMPK inhibits ACC by phosphorylation. Inhibition of ACC increases fatty acid oxidation by blocking the production of malonyl-CoA, the allosteric inhibitor of carnitine palmitoyl transferase 1. AMPK downregulates the expression of SREBP1c, a transcription factor that regulates different genes involved in lipid synthesis. Finally, APPL1 stimulates PPAR-α, another transcriptional factor controlling genes involved in fat oxidation. APPL1: Phosphotyrosine interaction, PH domain and leucine zipper containing 1; AMPK: AMP-activated protein kinase; ACC: Acetyl-CoA carboxylase; SREBP1: Sterol regulatory element-binding protein 1; PPAR-α: Peroxisome proliferator-activated receptor alpha; CPT-1: Carnitine palmitoyl transferase 1; ACOX: Acyl-CoA oxidase; LCAS: Long chain acyl-CoA synthetase.

Figure 2

Liver steatosis induced by down-regulation of adiponectin and its receptor in chronic hepatitis C virus infection. HCV core protein associated with the mitochondria leads to increased ROS that activates NF-κB. As a consequence of NF-κB activation, expression of a variety of cytokines is increased, including TNF-α, IL-6 and INF-γ. TNF-α modulates adipocytes and induces reduction in the production of adiponectin and its receptor. Reduced levels of adiponectin induce the increase in the synthesis of free fatty acids and reduce β-oxidation, causing liver steatosis in the HCV chronic infected patients. HCV: Hepatitis C virus; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; IL: Interleukin; IFN-γ: Interferon-γ; TNF-α: Tumour necrosis factor α; ROS: Reactive oxygen species.