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：
10606597
负责人：
GRACE L GUO
金额：
$ 31.4万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606597
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 Ketosteroids Knockout Mice Knowledge Length Ligand Binding Ligands 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 Receptor Inhibition Regulation Role STAT5B gene Signal Transduction Small Intestines Somatotropin Testing Toxic effect Transgenic Mice Transgenic Organisms Up-Regulation Xenobiotics antagonist 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肝疾病（NAFLD），其更严重的非酒精性脂肪性肝炎（NASH）为在美国增长最快的医疗伯内斯。需要有效且安全的药物来防止和/或治疗通常通过胆汁酸稳态失调而引发和/或恶化的纳什。胆汁酸稳态受到Farneoid X受体（FXR）的严格调节。肠道中的FXR激活高度诱导小鼠的成纤维细胞生长因子15（FGF15）和人类的FGF19。 FGF15/19是内分泌FGF 抑制胆汁酸合成和改善能量稳态的关键。 FXR配体和FGF19蛋白旨在治疗纳什的临床试验。 FGF15/19对药物代谢的影响尚不清楚。但是，这种知识对于确保安全的药物开发至关重要。性别特定表达的调节通过生长霍斯犬（GH）分泌模式和信号的药物代谢酶（DME）基因转录5b（STAT5B）途径的换能器和激活因子是众所周知的。在营养限制期间，GH 男性的分泌模式变为女性的分泌模式，这导致STAT5B激活较低，男性 - DME基因表达模式的女性转换。组成型雄激素受体（CAR； NR1I3），A 异源核接收器在调节DME基因表达中起关键作用。可以激活汽车直接通过配体结合或间接地通过抑制表皮生长因子受体（EGFR）。在体内，汽车是已知被两个男性高于女性的内源性拮抗剂所抑制：雄烷醇和Androstenol。我们已经生成了具有FGF15增益或功能丧失的新型鼠标模型：FGF15 转基因（FGF15 TG）和肠特异性FGF15敲除（FGF15INT - / - ）小鼠，并表明过表达 FGF15的摄入导致药物代谢中几种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特定性别基因表达模式开关。我们假设雄性小鼠的FGF15过表达发出了“营养的信号肝脏的限制”，肝脏降低了GH-STAT5B激活并导致DME的男女开关基因表达。该开关是通过减少汽车上的两个制动器来造成汽车激活的原因：（1）减少EGFR激活和（2）减少内源性汽车抑制剂。这个新颖的假设将被检验在两个独立但相关的特定目的中。 1。确定体内FGF15和FGF19的汽车激活体外，并确定FGF15/19导致汽车激活导致诱导的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基因表达和分子水平上的异生物核接收器激活非常重要，以确保更好的药物设计和预防毒性和药物相互作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice.

DOI：
10.1038/s41467-024-44924-w
发表时间：
2024-01-20
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Yang, Xue;Wang, Jianming;Chang, Chun-Yuan;Zhou, Fan;Liu, Juan;Xu, Huiting;Ibrahim, Maria;Gomez, Maria;Guo, Grace L.;Liu, Hao;Zong, Wei-Xing;Wondisford, Fredric E.;Su, Xiaoyang;White, Eileen;Feng, Zhaohui;Hu, Wenwei
通讯作者：
Hu, Wenwei

Bile Acid Regulates the Colonization and Dissemination of Candida albicans from the Gastrointestinal Tract by Controlling Host Defense System and Microbiota.

DOI：
10.3390/jof7121030
发表时间：
2021-11-30
期刊：
Journal of fungi (Basel, Switzerland)
影响因子：
0
作者：
Thangamani S;Monasky R;Lee JK;Antharam V;HogenEsch H;Hazbun TR;Jin Y;Gu H;Guo GL
通讯作者：
Guo GL

Suppression of Bile Acid Synthesis in a Preterm Infant Receiving Prolonged Parenteral Nutrition.

接受长期肠外营养的早产儿胆汁酸合成的抑制。

DOI：
10.1016/j.jceh.2021.04.007
发表时间：
2022
期刊：
Journal of clinical and experimental hepatology
影响因子：
3
作者：
Memon,Naureen;Lee,ChrisW;Herdt,Aimee;Weinberger,BarryI;Hegyi,Thomas;Carayannopoulos,MaryO;Aleksunes,LaurenM;Guo,GraceL;Griffin,IanJ
通讯作者：
Griffin,IanJ