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:
- 金额:$ 31.4万
- 依托单位:
- 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:
- 关键词:Adverse effectsAffectAndrostanolsAnimal ModelBile Acid Biosynthesis PathwayBile AcidsBody WeightCell LineClinical TrialsDataDiseaseDominant GenesDown-RegulationDrug InteractionsEndocrineEnsureEnzymesEpidermal Growth Factor ReceptorFGF19 geneFemaleFibroblast Growth FactorFutureGenderGene ExpressionGene Expression ProfileGenesGenetic TranscriptionHomeostasisHormone secretionHormonesHumanIn VitroIntestinesKetosteroidsKnockout MiceKnowledgeLengthLigand BindingLigandsLiverLiver diseasesMediatingMedicalMedicineMetabolic syndromeMolecularMouse StrainsMusNADPNuclear ReceptorsNuclear TranslocationNutrientOxidoreductasePathway interactionsPatternPharmaceutical PreparationsPhenotypePlayProtein DephosphorylationProteinsReceptor ActivationReceptor InhibitionRegulationRoleSTAT5B geneSignal TransductionSmall IntestinesSomatotropinTestingToxic effectTransgenic MiceTransgenic OrganismsUp-RegulationXenobioticsantagonistconstitutive androstane receptordehydroepiandrosteronedesigndrug developmentdrug metabolismhepatoma cellhormonal signalsimprovedin vivoinhibitorinnovationliver functionloss of functionmalemouse modelnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeuticsoverexpressionpreventreceptor
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.
项目总结
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:
- 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:
- 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:
- 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
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{{ truncateString('GRACE L GUO', 18)}}的其他基金
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:
10207687 - 财政年份:2020
- 资助金额:
$ 31.4万 - 项目类别:
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:
10286769 - 财政年份:2020
- 资助金额:
$ 31.4万 - 项目类别:
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:
10386929 - 财政年份:2020
- 资助金额:
$ 31.4万 - 项目类别:
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:
10601255 - 财政年份:2020
- 资助金额:
$ 31.4万 - 项目类别:
Role of Intestinal Bile Acid Signaling in Liver Diseases
肠胆汁酸信号在肝脏疾病中的作用
- 批准号:
10621137 - 财政年份:2017
- 资助金额:
$ 31.4万 - 项目类别:
Role of Intestinal Bile Acid Signaling in Liver Diseases
肠胆汁酸信号在肝脏疾病中的作用
- 批准号:
10257976 - 财政年份:2017
- 资助金额:
$ 31.4万 - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
8421637 - 财政年份:2013
- 资助金额:
$ 31.4万 - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
8697069 - 财政年份:2013
- 资助金额:
$ 31.4万 - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
9066738 - 财政年份:2013
- 资助金额:
$ 31.4万 - 项目类别:
FXR, nuclear receptors, and transcriptional regulation of liver homeostasis
FXR、核受体和肝脏稳态的转录调节
- 批准号:
8328025 - 财政年份:2011
- 资助金额:
$ 31.4万 - 项目类别:
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