Project Summary: Bile acids (BAs) are synthesized from cholesterol. BA synthesis is tightly controlled to
prevent incidence of diseases, such as cholestasis, gallstone disease, malabsorption, hypercholesterolemia, etc.
BAs are important for nutrient absorption and also function as endocrine hormones to regulate metabolic
homeostasis. BAs can activate farnesoid X receptor (FXR) and TGR5 to prevent non-alcoholic fatty liver disease
(NAFLD), diabetes and obesity. NAFLD is one of the most common chronic liver diseases worldwide, and is
often associated with obesity and diabetes. Forkhead box protein A3 (FOXA3) is a transcription factor. So far,
the role of hepatic FOXA3 in BA metabolism is completely unknown. Using both gain- and loss-of-function
approaches, we show that FOXA3 is regulated by FXR and may regulate BA metabolism and metabolic
homeostasis. In this project, we plan to investigate the role of hepatic FOXA3 in feedback regulation of BA
metabolism and the role of BA signaling in FOXA3-regulated metabolic homeostasis. We will use a number of
genetically modified mice as well as gain-of-function approaches to accomplish our goals.