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, 25% 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 is based on a novel discovered interaction and crosstalk between two central players in the control of energy metabolism, more specifically 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. Next to their known metabolic roles, independent findings have recently linked both proteins to NAFLD. In this project, the presence, activity and relevance of both proteins and their crosstalk will be thoroughly investigated in the context of NAFLD, both in human and murine samples. In addition, in accordance with the project‘s hypothesis that modulating the PPARα-ERRα tandem may ameliorate NAFLD progression, the therapeutic effect of combining PPARα and ERRα-targeting drugs will be evaluated in several murine models mimicking the human NAFLD profile.