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Hepatocyte caspase‐8 is an essential modulator of steatohepatitis in rodents
Author(s) -
Hatting Maximilian,
Zhao Gang,
Schumacher Fabienne,
Sellge Gernot,
Al Masaoudi Malika,
Gaβler Nikolaus,
Boekschoten Mark,
Müller Michael,
Liedtke Christian,
Cubero Francisco Javier,
Trautwein Christian
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26271
Subject(s) - steatohepatitis , hepatocyte , steatosis , fibrosis , liver injury , fatty liver , proinflammatory cytokine , inflammation , biology , cancer research , medicine , endocrinology , biochemistry , disease , in vitro
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. (H EPATOLOGY 2013;57:2189–2201)