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

FGF15/19 调节外源性核受体激活的肠肝串扰

基本信息

批准号：
10286769
负责人：
GRACE L GUO
金额：
$ 1.39万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286769
关键词：
Affect Androstanols Award Bile Acid Biosynthesis Pathway Bile Acids Clinical Trials Drug Interactions Endocrine Ensure Enzymes Epidermal Growth Factor Receptor FGF19 gene Female Fibroblast Growth Factor Gender Gene Expression Gene Expression Profile Genes Homeostasis Hormone secretion Human In Vitro Intestines Knock-out Knowledge Ligand Binding Ligands Liver Medical Medicine Molecular Mus Nuclear Receptors Nutrient Pathway interactions Pattern Pharmaceutical Preparations Play Proteins Receptor Activation Regulation Role STAT5B gene Signal Transduction Somatotropin Testing Toxic effect Transgenic Mice Transgenic Organisms Xenobiotics constitutive androstane receptor design drug development drug metabolism improved in vivo inhibitor/antagonist loss of function male mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel overexpression parent grant prevent receptor

项目摘要

Project Summary/Abstract (from Parent Grant) 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.

项目摘要/摘要（来自家长补助金）