Upregulation of human acyl-CoA synthetase 5 in fatty liver degeneration sensitizes for hepatocellular apoptosis

With the increasing incidence of obesity, diabetes and hypertriglyceridemia in Western countries, metabolic liver disease, in particular nonalcoholic fatty liver disease (NAFLD) has become a growing problem (Angulo and Lindor, 2002). Hepatocellular lipid accumulation which is mainly caused by excess dietary intake, increased rates of de novo lipogenesis and/ or decreased lipid export from hepatocytes is known to be the initial stage in the pathogenesis of NAFLD (Farrell and Larter, 2006). Steatosis hepatis in itself is a reversible condition but can progress to severe acute and chronic liver disease, including nonalcoholic steatohepatitis, fibrosis and cirrhosis (Friedman, 2008). The aim of the present study was to elucidate the role of acyl CoA synthetase 5 (ACSL5), a key enzyme in lipid metabolism, in the association of steatosis hepatis and hepatocellular apoptosis. Our current data reveal that ACSL5, a member of the ACSL gene family that is localized in the outer mitochondrial membrane, showed a significantly elevated expression level in fatty liver and concurrently induced an increased sensitization to hepatocellular apoptosis. By examining HepG2 cells as well as human liver tissue, we could show that the ACSL5 expression is significantly increased in both in vitro induced fatty degeneration of HepG2 and in vivo adipose liver tissue. Since ACSL5 is shown to be a sensitizing signal for apoptosis in enterocytes along the crypt villus axis (Gassler et al, 2008), ACSL5-overexpressing hepatocytes as well as control-transfected hepatocytes were treated with a panel of proapoptotic agents representing diverse cell death stimuli. The analysis revealed that ACSL5-overexpressing cells were substantially more sensitive to the apoptosis ligands TNFα, TRAIL and FAS than control-transfected cells. In conclusion, our findings give possible hints that ACSL5 could be a sensitizing signal for the induction of hepatocellular apoptosis in the pathogenesis of NAFLD.