Nonalcoholic fatty liver disease (NAFLD), with its more severe form, nonalcoholic steatohepatitis (NASH), is among the most rapidly growing medical burdens in the US. Effective and safe drugs are needed to prevent and/or treat NASH that is often initiated and/or worsened by dysregulation of bile acid homeostasis. Bile acid homeostasis is tightly regulated by farnesoid X receptor (FXR). FXR activation in the gut highly induces the fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. FGF15/19 are endocrine FGFs that are critical in suppressing bile acid synthesis and improving energy homeostasis. FXR ligands and FGF19 proteins are under clinical trials aiming to treat NASH. The effects of FGF15/19 on drug metabolism are unknown. However, this knowledge is critical to ensure safe drug development. Regulation of gender-specific expression of drug metabolizing enzyme (DME) genes by growth hormone (GH) secretion pattern and the signal transducer and activator of transcription 5b (STAT5b) pathway is well known. During nutrient restriction, GH secretion pattern in males is changed to that of females, which leads to lower STAT5b activation and a male- to-female switch of the pattern of DME gene expression. The constitutive androstane receptor (CAR; NR1I3), a xenobiotic nuclear receptor, plays a pivotal role in regulating DME gene expression. CAR can be activated directly by ligand binding or indirectly by inhibition of epidermal growth factor receptor (EGFR). In vivo, CAR is known to be inhibited by two endogenous antagonists that are higher in males than in females: androstanol and androstenol. We have generated novel mouse models with FGF15 gain- or loss-of-function: Fgf15 transgenic (Fgf15 Tg) and intestine-specific Fgf15 knockout (Fgf15int-/-) mice, and showed that overexpression of FGF15 led to induction of the expression of several CAR specific target genes in drug metabolism. Additional evidence suggests that this induction may be from a nutrient restriction and gender specific gene expression pattern switch. We hypothesize that FGF15 overexpression in male mice sends a signal of ?nutrient restriction? to the liver, which decreases GH-STAT5b activation and results in a male-to-female switch of DME gene expression. This switch is responsible for CAR activation by decreasing two brakes on CAR: (1) decreasing EGFR activation and (2) reducing endogenous CAR inhibitors. This novel hypothesis will be tested in two independent but related specific aims. 1. Determine CAR activation by FGF15 in vivo and FGF19 in vitro, and determine to what extent CAR activation is responsible for inducing DME genes by FGF15/19. 2. Determine the molecular mechanism of CAR activation in the male Fgf15 Tg mice. Understanding the mechanisms by which the bile acids-FGF15/19 signaling affects gender specific DME gene expression and xenobiotic nuclear receptor activation at the molecular level is highly significant to ensure better medicine design and to prevent toxicities and drug-drug interaction.
The current study will shed mechanistic light into understanding the role of fibroblast growth factor 15 and 19 (FGF15/19), mainly induced by farnesoid X receptor in the small intestine by bile acids, in regulating gender- specific drug metabolizing enzyme gene expression and activating a xenobiotic nuclear receptor, constitutive androstane receptor, to induce genes in drug metabolism. Activation of xenobiotic nuclear receptors by gut- derived endocrine factors is significant and novel. These results will help to provide mechanistic understanding of how FGF15/19 regulates liver functions and, most importantly, this knowledge will shed light on designing new medicines to treat liver diseases, including nonalcoholic steatohepatitis, while preventing adverse effects and drug-drug interactions.
