Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents

Maximilian Hatting, Gang Zhao, Fabienne Schumacher, Gernot Sellge, Malika Al Masaoudi, Nikolaus Gaβler, Mark Boekschoten, Michael Müller, Christian Liedtke, Francisco Javier Cubero, Christian Trautwein

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65 Citations (Scopus)

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. Conclusion: 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).
Original languageEnglish
Pages (from-to)2189-2201
Number of pages13
JournalHepatology
Volume57
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Animals
  • Apoptosis
  • Caspase 8
  • Fatty Liver
  • Fibrosis
  • Hepatocytes
  • Lipid Metabolism
  • Liver
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress

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