Novel regulators of hepatic energy metabolism

Metabolic syndrome is a rapidly increasing global epidemic with a prevalence of 20 to 25% in the adult population. The metabolic syndrome strongly increases the risk of developing cardiovascular disease, which remains the leading cause of death worldwide. The hepatic manifestation of the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD), which covers a spectrum of disease stages ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Despite great advances in understanding the pathophysiology of these diseases, there are currently no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved drugs for the treatment of NAFLD. Currently, many drugs are developed and in the pipeline. One promising group of hormone-based drugs is based on several members of the fibroblast growth factor (FGF) family with strong metabolic effects, including amelioration of hepatic steatosis. In our research into the mechanisms underlying the hepatic lipid lowering effects of FGF1, we have recently identified several interesting downstream targets. This thesis investigates the individual role of these FGF targets in hepatic lipid metabolism and their potential in treating NAFLD. We have studied the biological function and molecular mechanisms of these regulators and their involvement in hepatic energy metabolism and hepatic function. Using experimental approaches, including mouse models and in vitro systems, we uncovered new functions and angles to guide future research efforts to understand hepatic energy metabolism and combat NAFLD.