Repin1 and Resolvines - provocation and resolution of "silent and sterile" inflammation (inflammasome) in the progression of chronic liver diseases to HCC

• Applicant: Dr. Kerstin Abshagen
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281273087

Metabolic effects, oxidative stress, and an imbalance of pro- and anti-inflammatory cytokines are of particular importance in the progression of fatty liver to hepatocellular carcinoma (HCC). During liver inflammation activation of the NLRP3 inflammasome plays a crucial role in the pathogenesis of chronic liver diseases. Therefore, reduction of the inflammatory state is of high significance for prevention and therapy of liver diseases. In this study we analyze (i) the correlation between lipid modulators, such as Repin1 and lipid mediators (resolvines), (ii) their regulation of the sterile inflammation in the progression of chronic liver diseases to HCC, (iii) their significance in humans, and (iv) aspects for prevention and therapy. The aim of this study is to evaluate whether hepatic deficiency of Repin1 attenuates progression of fatty liver to HCC by modulating the NLRP3-mediated inflammatory response in a clinically relevant experimental NASH-Fibrosis-HCC mouse model. In this context, functional relationships between Repin1-induced generation of metabolic alarm signals and a consecutive activation of NLRP3 as well as a perpetuation of the hepatic inflammation due to the lack of resolvines should be analyzed. We further focus on adiponectin as a common factor and regulator of both signaling pathways, resolvines, and NLRP3. Moreover, it should be evaluated whether a liver-specific siRNA-mediated deficiency of Repin1 or NLRP3 as well as a supply of anti-inflammatory mediators (n-3 fatty acid (diet), resolvines) represent therapeutic and preventive options for the treatment of chronic liver diseases.

• DFG Programme: Research Grants