Functional characterization of the orphan nuclear receptors TR2 and TR4 in the pathophysiology of hepatic steatosis and fibrosis

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide and an important cause of end-stage liver disease and hepatocellular carcinoma. Its pathogenesis and progression have been linked to overnutrition and obesity, but current therapeutic options are limited. Since nuclear hormone receptors are powerful physiological regulators as well as ideal drug targets, we have used genomic approaches to identify those receptors which may play a role during diet-induced hepatic steatosis and fibrosis. These studies have revealed TR2 and TR4 as novel candidates controlling liver metabolism and disease. We therefore propose to apply mouse genetics and genomics approaches together with metabolomics, proteomics and detailed phenotypic and histological analyses to functionally characterize these two related transcription factors. This proposal also includes the identification transcriptional target genes and metabolic pathways controlled by TR2 and TR4 in hepatocytes.

DFG Programme Research Grants