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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（来自家长资助）非酒精性脂肪性肝病 (NAFLD) 及其更严重的非酒精性脂肪性肝炎 (NASH) 是是美国增长最快的医疗负担之一。需要有效且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。胆汁酸体内平衡受到法尼醇 X 受体 (FXR) 的严格调节。肠道中的 FXR 激活高度诱导小鼠中的成纤维细胞生长因子 15 (FGF15) 和人类中的 FGF19。 FGF15/19 是内分泌 FGF 对于抑制胆汁酸合成和改善能量稳态至关重要。 FXR 配体和 FGF19 蛋白正在进行旨在治疗 NASH 的临床试验。 FGF15/19 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。特定性别表达的监管生长激素 (GH) 分泌模式和信号对药物代谢酶 (DME) 基因的影响转录转导子和转录激活子 5b (STAT5b) 途径是众所周知的。在营养限制期间，GH 雄性的分泌模式改变为雌性，这导致 STAT5b 激活较低，并且雄性- DME 基因表达模式向女性的转变。组成型雄甾烷受体（CAR；NR1I3）异生核受体在调节 DME 基因表达中起着关键作用。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是已知受到两种内源性拮抗剂的抑制，这两种拮抗剂在男性中的含量高于女性：雄甾烷醇和雄甾烯醇。我们已经生成了具有 FGF15 功能获得或丧失的新型小鼠模型：Fgf15 转基因 (Fgf15 Tg) 和肠道特异性 Fgf15 敲除 (Fgf15int-/-) 小鼠，并表明过度表达 FGF15 导致药物代谢中几个 CAR 特异性靶基因的表达诱导。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切换。我们假设雄性小鼠中 FGF15 过度表达会发出“营养”信号 “限制”到肝脏，从而减少 GH-STAT5b 激活并导致 DME 从男性转变为女性基因表达。该开关负责通过减少 CAR 上的两个制动器来激活 CAR：(1) 减少 EGFR 激活和 (2) 减少内源性 CAR 抑制剂。这一新颖的假设将得到检验两个独立但相关的具体目标。 1. 确定体内 FGF15 和体内 FGF19 的 CAR 激活体外，并确定 CAR 激活在多大程度上负责 FGF15/19 诱导 DME 基因。 2. 确定雄性 Fgf15 Tg 小鼠中 CAR 激活的分子机制。了解胆汁酸-FGF15/19 信号传导影响性别特异性 DME 基因表达的机制分子水平上的异生核受体激活对于确保更好的药物非常重要设计并防止毒性和药物间相互作用。