Hatting, MaximilianGang, ZhaoSchumacher, FabienneSellge, GernotMasaoudi, Malika AlGassler, NikolausBoekschoten, MarkMüller, MichaelLiedtke, ChristianCubero Palero, Francisco JavierTrautwein, Christian2024-02-022024-02-022012-12-14Hatting M, Zhao G, Schumacher F, Sellge G, Al Masaoudi M, Gaβler N, Boekschoten M, Müller M, Liedtke C, Cubero FJ, Trautwein C. Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. Hepatology. 2013 Jun;57(6):2189-201. doi: 10.1002/hep.26271. Epub 2013 May 6. PMID: 23339067.1527-335010.1002/hep.26271https://hdl.handle.net/20.500.14352/98118From the 1 Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany; 2 Institute of Pathology, University Hospital, RWTH Aachen, Germany; 3 Nutrition, Metabolism & Genomics group, Wageningen University, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Received August 13, 2012; accepted December 14, 2012.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).engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.2627123339067https://pubmed.ncbi.nlm.nih.gov/23339067/open access616.1/.9Ciencias BiomédicasBiologíaBiología celular (Biología)Biología molecular (Biología)Inmunología24 Ciencias de la Vida2407 Biología Celular2415 Biología Molecular2412 Inmunología