Pharmaceutical Sciences and Pharmacogenomics

Metabolism dysfunction associated fatty liver disease (MASLD), with its more severe form, metabolism dysfunction associated steatohepatitis (MASH), is among the most rapidly growing medical burdens in the US. Effective and safe drugs are needed to treat MASH that is often initiated and/or worsened by dysregulation of bile acid (BA) homeostasis. BA homeostasis is tightly regulated by farnesoid X receptor (FXR) that 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 BA synthesis and improving energy homeostasis, and under clinical trials aiming to treat BA related disorders. The effects of FGF15/19 on drug metabolism are unknown; however, are critical to ensure safe drug development. 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). We have generated novel genetically modified mouse models with FGF15 gain- or loss-of-function, 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 sex 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 is highly significant to ensure better medicine design and to prevent toxicities and drug-drug interaction.