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

• 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
• 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

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.

项目总结 非酒精性脂肪性肝病(NAFLD)及其更严重的形式非酒精性脂肪性肝炎(NASH)是 这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 动态平衡受到法尼醇X受体(FXR)的严格调控。肠道中FXR的激活高度诱导 成纤维细胞生长因子15(FGF15)在小鼠和FGF19在人类。FGF15/19是内分泌FGFs，它们是 在抑制胆汁酸合成和改善能量平衡方面起关键作用。FXR配体与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。对不同性别表达的监管 生长激素(GH)分泌模式和信号对药物代谢酶基因的影响 转录转导和激活因子5b(STAT5b)途径是众所周知的。在营养限制期间，生长激素 男性的分泌模式改变为女性的分泌模式，导致STAT5b活性降低，男性- DME基因表达模式的雌雄转换。构成雄烷受体(CAR；NR1I3)，a 异源生物核受体在调节DME基因表达中起着关键作用。Car可以被激活 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，这两种内源性拮抗剂男性的比例高于女性：雄烷醇 和雄烯醇类。我们已经产生了具有FGF15增减功能的新型小鼠模型：Fgf15 转基因(Fgf15Tg)和肠道特异性Fgf15基因敲除(Fgf15int-/-)小鼠，并显示过表达 在药物代谢过程中，FGF15诱导了几个CAR特异性靶基因的表达。 更多的证据表明，这种诱导可能来自营养限制和性别特异性基因。 表达式模式切换。我们假设FGF15在雄性小鼠体内过表达发出一种“营养”的信号 对肝脏的限制，这会降低GH-STAT5b的激活，并导致DME从男性到女性的转换 基因表达。此开关负责通过减少汽车上的两个刹车来激活汽车：(1) 降低EGFR活性；(2)减少内源性CAR抑制剂。这一新的假设将得到检验。 有两个独立但又相互关联的具体目标。1.测定体内FGF15和FGF19对CAR的激活 并确定CAR激活在多大程度上对FGF15/19诱导DME基因起作用。 确定雄性Fgf15转基因小鼠CAR激活的分子机制。了解 胆汁酸-FGF15/19信号影响性别特异性DME基因表达和 异种生物核受体在分子水平上的激活对确保更好的药物具有重要意义 设计并防止毒副作用和药物-药物相互作用。

项目成果

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)
• 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