Impact of cyclooxygenase 2-dependent generated prostaglandin E2 and other prostanoids in the development of diet-induced non-alcoholic steatohepatitis (NASH)

• Applicant: Professorin Dr. Janin Henkel-Oberländer
• Subject Area: Nutritional Sciences ; Biochemistry
• Term: from 2013 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245981492

The worldwide prevalence of obesity and the ensuing diseases like the metabolic syndrome and type2 diabetes is increasing rapidly. Non-alcoholic fatty liver disease (NAFLD), which is characterized by an excessive hepatic lipid accumulation, is defined as the hepatic manifestation of the metabolic syndrome and the main reason for functional liver diseases. Some patients develop the severe form of non-alcoholic steatohepatitis (NASH), where steatosis isaccompanied by inflammation and fibrosis, which results in an increased risk for cirrhosis, liver cancer and organ failure. Beside cytokines, prostaglandins like prostaglandin E2 (PGE2) play a Major role in the regulation of the inflammation. Prostaglandins are bioactive lipids that are synthesized cyclooxygenase 2 (Cox2)-dependently during inflammatory processes and can act to amplify or to attenuate inflammation. Within the scope of the project HE-7032/1-1 a NASHinducing diet was established, which induced hepatic steatosis with inflammation and fibrosis as well as obesity and insulin resistance in wildtype mice and thus exhibited all clinical parameters of human NASH in the metabolic syndrome. In these mice, as well as in patients with NASH, the hepatic expression of Cox2 and mPGES1, the Cox2- downstream enzyme in PGE2-synthesis, was enhanced, indicating a local increase in PGE2 formation. PGE2 can inhibit the expression of the pro-inflammatory cytokine TNFα. In livers of mPGES1-deficient mice fed a NASH-inducing diet, the induction of TNFα was increased compared to wild type mice, resulting in more pronounced hepatocyte apoptosis. Against the expectations, a deficiency in mPGES1 only lowered the hepatic PGE2 levels but was not sufficient to completely eliminate the diet-induced hepatic PGE2 generation. Consequently, the minor differences in hepatic PGE2 levels between the genotypes did not result in a more severe diet-induced hepatic inflammation. However, in primary macrophages incubated with the Cox2-inhibitor indomethacin the inflammation-mediated increase in PGE2 production was completely abrogated. The follow-up project will focus on theimpact of the Cox2-dependently generated prostanoids like PGE2 in the development of diet-induced NASH. Mice with a specific deletion of Cox2 in macrophages, hepatocytes or both cell types as well as their respective controls will receive standard and NASH-inducing diets and will be characterized regarding the development and progression of NASH. Parallel in vitro experiments with the macrophage populations and hepatocytes from the individual genotypes will help to determine the pro- or anti-inflammatory role of Cox2 on a cellular level. Additionally, the results will be validated in human liver probes. A second part of the project will investigate the heterogeneity of different macrophage populations in mice livers with diet-induced NASH. These distinct macrophages should be isolated and characterized regarding their sensitivity to prostanoids like PGE2.

• DFG Programme: Research Grants