In vitro and in vivo analyses of the specific role of NLRP3 in the pathogenesis of fibrosis in non-alcoholic Steatohepatitis

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Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) show an increasing prevalence worldwide, mainly because of an increased prevalence of the well-established risk factors obesity and diabetes mellitus. Years after the onset of NAFLD/NASH a subset of patients progresses to liver fibrosis and liver cirrhosis and is at high risk of developing hepatocellular carcinoma (HCC). New data predict NASH to be the most common cause for the development of HCC worldwide within the next years.The pathophysiological pathways of progression of NASH leading to liver fibrosis and liver cirrhosis are not fully clarified up to now. The most common pathophysiological model implicates a central role of hepatic inflammation, especially the NLRP3 inflammasome. Published data of the guest laboratory of Prof. Feldstein showed a major importance of NLRP3 inflammasome activation in developing liver fibrosis in the context of NASH. Persistent activation of NLRP3 leads to continuous hepatic inflammation and activation of hepatic stellate cells (HSC) as well as liver fibrosis.This proposal hypothesizes the molecular activation of HSC via NLRP3 as the main signalling pathway during fibrogenesis in NASH. Using knock-in and knockout mice models as well as in vitro experiments the main aim of this research project is to identify the mechanisms and signalling of NLRP3-dependent activation of HSC during fibrogenesis.The data obtained by this research project will contribute to a better understanding of fibrogenesis in NASH and may reveal a new therapeutic strategy for the medical treatment of NASH patients.