Charakterisierung der molekularen Mechanismen des Adipokins Adiponectin bei der Nicht-alkoholischen Steatohepatitis (NASH)
Aim of this study was to identify the role of adiponectin in the development and progression of non-alcoholic steatohepatitis in the liver. Thereby the effect of adiponectin on activin A and follistatin in steatotic and non steatotic heatocytes was discovered and the influence of adiponectin on TGF-β action was investigated. In addition the role of chemerin in NAFLD and the effect of adiponectin on the expression of this protein and its receptor CMKLR1 in hepatocytes was discovered. Adiponectin
... overed. Adiponectin plasma levels were reduced in steatotic patients and mice with diet induced NASH and fibrosis. The hepatic level of AdipoR2 was also reduced in the fatty liver. Therefore we can assume that adiponectin signalling is reduced in NAFLD. Adiponectin induced activin A and reduced its inhibitor follistatin in an in-vitro culture of primary human hepatocytes. Preincubation of hepatocytes with palmitic acid prevented the inductive effect of adiponectin on activin A. It was shown, that the palmitic acid induced TGF-β in the supernatants of the cells and TGF-β prevented in an Alk5 and SMAD3 dependent signalling pathway the adiponectin effect on activin A. Further experiments showed that adiponectin induced BAMBI in hepatocytes and hepatic stellate cells in-vitro. An overexpression of BAMBI reduced the TGF-β driven elevation of CTGF in hepatocytes. In addition adiponectin itself diminished the protein level of this TGF-β activator in a PPAR-α dependent manner. Adiponectin was also able to reduce the TGF-β induced phosphorylation of SMAD2 and SMAD3 and the TGF-β induced induction of CTGF in hepatocytes. It was also shown, that chemerin is highly expressed in human hepatocytes. In these cells this protein inhibits the insulin action. Adiponectin lowers the secretion of chemerin from hepatocytes, but induced the level of CMKLR1 in these cells. Therefore adiponectin could be able to induce the action of chemerin and other CMKLR1 ligands like resolvin.