These authors contributed equally as first authors.
Steatohepatitis/Metabolic Liver Disease
Article first published online: 6 MAY 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 57, Issue 6, pages 2189–2201, June 2013
How to Cite
Hatting, M., Zhao, G., Schumacher, F., Sellge, G., Al Masaoudi, M., Gaβler, N., Boekschoten, M., Müller, M., Liedtke, C., Cubero, F. J. and Trautwein, C. (2013), Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. Hepatology, 57: 2189–2201. doi: 10.1002/hep.26271
Potential conflict of interest: Nothing to report.
Supported by a grant from the IZKF Aachen (Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at RWTH Aachen University), the Deutsche Forschungsgemeinschaft (SFB/TRR 57) and the Bundesministerium für Bildung und Forschung (ObiHep grant 01KU1214B).
- Issue published online: 12 JUN 2013
- Article first published online: 6 MAY 2013
- Accepted manuscript online: 21 JAN 2013 11:50PM EST
- Manuscript Accepted: 14 DEC 2012
- Manuscript Received: 13 AUG 2012
- IZKF Aachen (Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at RWTH Aachen University)
- Deutsche Forschungsgemeinschaft. Grant Number: SFB/TRR 57
- Bundesministerium für Bildung und Forschung. Grant Number: 01KU1214B
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 (Casp8Δhep) 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 Casp8Δhep 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 Casp8Δhep 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)