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DOI: 10.1055/s-0032-1331949
Hepatocyte specific deletion of Mesenchymal-epithelial transition factor (c-Met) leads to the development of severe non-alcoholic-steatohepatitis (NASH) in a murine NASH model
Background: One of the fastest growing medical problems in industrial countries is the metabolic syndrome including non-alcoholic-fatty-liver disease (NAFLD). The spectrum of NAFLD includes NASH. NASH is characterized by hepatic fat accumulation leading to an increase of oxidative stress and apoptosis resulting in severe inflammation and finally liver cirrhosis and hepatocellular carcinoma. As a consequence, NASH-related liver transplantation rates are increasing. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor is known to be anti-apoptotic in hepatocytes. Moreover, apoptosis plays an important role in the progression of NASH.
Aim: Thus, our aim was to characterize the role of c-met during the development of NASH.
Methods: Hepatocyte specific c-met knockout mice (c-metΔhepa) using the cre-loxP system and wildtype control mice (c-metloxPloxP) were fed with Methionin Choline Deficient Diet (MCD) for 4 weeks.
Results: After 4 weeks of MCD feeding c-MetΔhepa mice showed massive steatosis and increased infiltrating immune cells in hepatic H&E stainings compared to c-MetloxPloxP littermates. These results were confirmed by an Oil Red O Staining and by detecting a higher content of hepatic triglycerides in c-MetΔhepa animals. Additionally, c-MetΔhepa showed higher transaminase levels. To investigate underlying molecular mechanisms we performed gene array analysis. Here we could demonstrate that genes involved in fatty acid metabolism were strongly upregulated in livers of c-MetΔhepa mice. Consequently, c-MetΔhepa mice showed significantly more TUNEL positive cells and more superoxidanione production than c-MetloxPloxP animals. Infiltrating immune cells were studied by flow cytometry analysis of intrahepatic leukocytes and by immunofluorescence stainings. In contrast to c-MetloxPloxP mice, large fractions of neutrophils, macrophages and cytotoxic T cells could be identified in c-MetΔhepa littermates. Further analyses also revealed higher collagen disposition in c-MetΔhepa livers indicating an earlier onset of liver fibrosis.
Conclusion: Hepatocyte specific c-Met deletion causes severe hepatosteatosis in the MCD model. This is associated with increased oxidative stress and hepatocyte apoptosis triggering augmented liver infiltration with neutrophils, macrophages and cytotoxic T cells leading to enhanced liver fibrosis.