Adiponectin inhibits steatotic CD95/Fas up-regulation by hepatocytes: Therapeutic implications for hepatitis C

Background/Aims Steatosis may trigger hepatocytes to up-regulate CD95/Fas thereby increasing susceptibility to apoptosis, inflammation and fibrosis. We investigated this concept and potential roles of adiponectin and its receptors (AdipoR1; AdipoR2) in chronically HCV-infected patients. Methods In 98 HCV+ patients and 20 controls, sera were tested for HCV genotypes, FFAs, adiponectin and the M30 apoptosis indicator, and biopsies were evaluated for steatosis/inflammation/fibrosis, CD95/Fas (mRNA/protein), adiponectin (mRNA/protein), AdipoR1/-R2 (mRNA) and M30 (protein). We also questioned whether adiponectin protects HepG2 hepatoblastoma cells from FFA-triggered CD95/Fas up-regulation and apoptosis. Results Patients [HCV clades 1 (78%), 2 (3%) and 3 (19%)] revealed increased FFA and adiponectin serum levels ( p = .005). Hepatocyte CD95/Fas up-regulation correlated with steatosis, inflammation and fibrosis ( p = .004). Advanced fibrosis correlated significantly ( p = .05) with serum M30. Liver adiponectin correlated with steatosis ( p = .016), CD95/Fas ( p < .001) and inflammation/fibrosis. Hepatocyte AdipoR2 mRNA specifically correlated with serum adiponectin and steatosis ( p = .003), while hepatocyte AdipoR1 mRNA dropped in pronounced fibrosis ( p = .060). Finally, adiponectin protected HepG2 cells from FFA-triggered CD95/Fas expression and induction of apoptosis ( p = .0396). Conclusions In chronic HCV infection, steatosis up-regulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. The physiologic countermeasure of adiponectin up-regulation may offer clues for future therapeutic intervention.