# Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $312,000

## Abstract

PROJECT SUMMARY
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 ...

## Key facts

- **NIH application ID:** 10050282
- **Project number:** 1R01GM135258-01A1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** GRACE L GUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $312,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050282

## Citation

> US National Institutes of Health, RePORTER application 10050282, Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation (1R01GM135258-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10050282. Licensed CC0.

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