title: Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents.
abstract: In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Δhep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Δhep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Δhep) livers.
  
  
  CONCLUSIONS
  Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201).
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
authors: Maximilian
authors: M
authors: Hatting
authors: Gang
authors: G
authors: Zhao
authors: Fabienne
authors: F
authors: Schumacher
authors: Gernot
authors: G
authors: Sellge
authors: Malika
authors: M
authors: Al Masaoudi
authors: Nikolaus
authors: N
authors: Gaβler
authors: Mark
authors: M
authors: Boekschoten
authors: Michael
authors: M
authors: Müller
authors: Christian
authors: C
authors: Liedtke
authors: Francisco Javier
authors: FJ
authors: Cubero
authors: Christian
authors: C
authors: Trautwein
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D005355:Fibrosis; D022781:Hepatocytes / Q000201:enzymology*; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress
chemical_list: C505526:Casp8 protein, mouse; D053181:Caspase 8