Characterization of the PPARα-ERRα interaction and crosstalk in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a continuous spectrum of metabolic liver disorders, ranging from hepatic fat accumulation to the presence of inflammation, fibrosis and cirrhosis (referred to as non-alcoholic steatohepatitis (NASH)). Worldwide, 24% of the population suffers from these hepatic disorders, which are often correlated with obesity. Despite the fact that uncontrolled NASH can lead to severe health issues to even death, currently there are no effective therapeutic strategies available to halt this deleterious progression. The current project focuses on a novel discovered interaction between two central players in the control of energy metabolism. More specifically, a combination of molecular tools will enable to characterize the interaction between PPARα, which is the target of lipid profile-normalizing drugs already on the market, and ERRα, which is present in high amounts in the liver and involved in a proper control of energy pathways. These molecular insights will be used for the development of interaction-breaking approaches, which may eventually lead to a targeted therapy against the progressive form of NASH. Finally, in accordance with the project‘s hypothesis that modulating the PPARα-ERRα interaction may ameliorate NAFLD progression, the therapeutic effect of combining PPARα and ERRα-targeting drugs will be evaluated in a mouse model mimicking the human NAFLD profile.