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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：
10601255
负责人：
GRACE L GUO
金额：
$ 7万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10601255
关键词：
Adverse effects Affect Androstanols Animal Model Bile Acid Biosynthesis Pathway Bile Acids Body Weight Cell Line Clinical Trials Data Disease Dominant Genes Down-Regulation Drug Interactions Endocrine Ensure Enzymes Epidermal Growth Factor Receptor FGF19 gene Female Fibroblast Growth Factor Future Gender Gene Expression Gene Expression Profile Genes Genetic Transcription Homeostasis Hormone secretion Hormones Human In Vitro Intestines Knock-out Knockout Mice Knowledge Lead Length Ligand Binding Ligands Light Liver Liver diseases Mediating Medical Medicine Metabolic syndrome Molecular Mouse Strains Mus NADP Nuclear Receptors Nuclear Translocation Nutrient Oxidoreductase Pathway interactions Pattern Pharmaceutical Preparations Phenotype Play Protein Dephosphorylation Proteins Receptor Activation Regulation Role STAT5B gene Signal Transduction Small Intestines Somatotropin Steroids Testing Toxic effect Transgenic Mice Transgenic Organisms Up-Regulation Xenobiotics antagonist base constitutive androstane receptor dehydroepiandrosterone design drug development drug metabolism hepatoma cell hormonal signals improved in vivo inhibitor innovation liver function loss of function male mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics overexpression prevent receptor

项目摘要

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 to prevent toxicities and drug-drug interaction.

项目摘要非酒精性脂肪性肝病（NAFLD），其更严重的形式，非酒精性脂肪性肝炎（NASH），是美国增长最快的医疗负担之一。需要有效和安全的药物来预防和/或治疗通常由胆汁酸稳态失调引发和/或恶化的NASH。胆汁酸体内平衡受法尼醇X受体（FXR）的严格调节。肠道中的FXR激活高度诱导了小鼠中的成纤维细胞生长因子15（FGF 15）和人中的FGF 19。FGF 15/19是内分泌FGF，在抑制胆汁酸合成和改善能量平衡方面至关重要。FXR配体和FGF 19蛋白正在进行旨在治疗NASH的临床试验。FGF 15/19对药物代谢的影响尚不清楚。然而，这些知识对于确保安全的药物开发至关重要。性别特异性表达的调节药物代谢酶（DME）基因的生长激素（GH）分泌模式和信号转导子和转录激活子5 b（STAT 5 b）途径是众所周知的。在营养限制期间，GH 男性的分泌模式改变为女性的分泌模式，这导致STAT 5 b活化降低，男性- DME基因表达模式向雌性的转换。组成型雄烷受体（CAR; NR 1 I3），外源性核受体，在调控DME基因表达中起关键作用。可以激活CAR 直接通过配体结合或间接通过抑制表皮生长因子受体（EGFR）。在体内，CAR 已知被两种内源性拮抗剂抑制，雄性比雌性高：雄甾烷醇和雄甾烯醇。我们已经产生了具有FGF 15功能获得或丧失的新型小鼠模型：转基因（Fgf 15 Tg）和精氨酸特异性Fgf 15敲除（Fgf 15 int-/-）小鼠，并显示过表达 FGF 15的表达导致在药物代谢中诱导几种CAR特异性靶基因的表达。其他证据表明，这种诱导可能来自营养限制和性别特异性基因表情模式转换。我们推测，FGF 15在雄性小鼠中的过表达传递了“营养”信号，限制”肝脏，这降低了GH-STAT 5 b的激活，并导致DME的男性到女性的转换基因表达。此开关负责通过降低CAR上的两个制动器来激活CAR：（1）减少EGFR活化和（2）减少内源性CAR抑制剂。这一新的假设将得到验证两个独立但相关的具体目标。1.测定体内FGF 15和体内FGF 19对CAR的激活作用。体外，并确定CAR活化在多大程度上负责通过FGF 15/19诱导DME基因。2. 确定雄性Fgf 15 Tg小鼠中CAR活化的分子机制。了解胆汁酸-FGF 15/19信号传导影响性别特异性DME基因表达的机制，在分子水平上的异生物质核受体活化对于确保更好的药物具有高度意义设计和预防毒性和药物相互作用。