Fibroblast growth factor 15 (Fgf15) is the mouse ortholog of human FGF19. FGF15/19 are endocrine FGFs produced in the distal small bowel that govern whole-body homeostasis through the regulation of bile acids, hepatic glucose, and lipid metabolism. Recognizing the pleotropic role of FGF15/19 in regulating hepatobiliary function, pharmaceutical companies have launched research programs testing the therapeutic potential of FGF19 to treat numerous liver and metabolic diseases. Nonalcoholic steatohepatitis (NASH) is a disease that has been characterized by the disregulation of many of the metabolic pathways governed by FGF19. NASH is rapidly becoming a major health issue in the United States as it affects approximately 3-12% of the population. There are currently no pharmaceutical therapies for NASH patients. NASH is projected to overtake hepatitis C virus as leading indication of liver transplant in the United States. The bile acid-FXR- FGF15/19 pathway is being investigated for its potential for use as a therapeutic intervention of NASH, with FGF19 protein functioning as a prospective treatment. Our preliminary data suggests that FGF19 protein alters drug-metabolizing enzymes. Alterations to drug-metabolizing enzymes can lead to drug-drug interactions, in which a perpetrator drug alters the disposition and/or action of a victim drug when taken in combination. Drug-drug interactions can lead to the loss of efficacy or toxicity in patients, therefore it is important to properly evaluate the potential of new therapies to alter drug-metabolizing enzymes.
The research aims i n this proposal will investigate the potential of FGF15/19 to bring about changes in drug- metabolizing enzymes.
Aim 1 will descriptively characterize the observed variations and delineate the role of specific xenobiotic receptors. In addition, we will examine whether or not the observed changes in drug- metabolizing enzymes from our preliminary data affect the rate at which probe substrates are metabolized.
Aim 2 will use in vitro and in vivo methodologies to elucidate the mechanism by which these changes are induced. Through the completion of the research and training described in this F31 Fellowship, the Principal Investigator will be trained in basic and translational biomedical research and will be prepared to conduct independent research, which is in line with the mission and vision of the National Institute of Diabetes and Digestive and Kidney Diseases.
Nonalcoholic steatohepatitis is a growing health concern worldwide and is projected to become the leading indication for liver transplantation in the United States. The Bile Acid-FXR-FGF19 pathway has emerged as a potential therapeutic target for this disease. The goal of this proposal to better understand safety associated with pharmaceutical targets within this pathway.
