FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho

doi:10.1210/me.2015-1226

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	FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho
	Fu, Ting 3; Kim, Young-Chae 3; Byun, Sangwon 3; Kim, Dong-Hyun 3; Seok, Sunmi 3; Suino-Powell, Kelly 1; Xu, H. Eric1,2 ; Kemper, Byron 3; Kemper, Jongsook Kim 3
刊名	MOLECULAR ENDOCRINOLOGY
	2016-01
卷号	30 期号:1 页码:92-103
ISSN号	0888-8809
DOI	10.1210/me.2015-1226
文献子类	Article
英文摘要	The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF) 15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, beta-Klotho (beta KL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-alpha, at FGF15-signaling component genes, particularly beta KL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of beta KL-dependent increased protein stability. Both FGF receptor 4 and beta KL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF19 signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of beta KL in FXR-lacking hepatocytes partially restored FGF19 signaling and inhibition by FGF19 of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic beta KL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF19 treatment enhanced FGF19 signaling, which was abolished by transcriptional inhibition or beta KL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/19 action that orchestrates transient induction of hepatic beta KL and intestinal Fgf15/19 in a temporally correlated manner.
资助项目	National Institutes of Health[DK062777] ; National Institutes of Health[DK095842]
WOS关键词	BILE-ACID SYNTHESIS ; FARNESOID-X-RECEPTOR ; CHOLESTEROL 7-ALPHA-HYDROXYLASE GENE ; METABOLISM ; EXPRESSION ; PATHWAY ; MICE ; HEPATOCYTES ; OBESITY ; IDENTIFICATION
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	ENDOCRINE SOC
WOS记录号	WOS:000377205900009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276226]
专题	药物靶标结构与功能中心
通讯作者	Kemper, Jongsook Kim
作者单位	1.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 2.Chinese Acad Sci, Van Andel Res Inst Shanghai Inst Mat Med, Chinese Acad Sci Key Lab Receptor Res, Ctr Struct & Funct Drug Targets,Shanghai Inst Mat, Shanghai 201203, Peoples R China 3.Univ Illinois, Dept Mol & Integrat Physiol, 407 South Goodwin Ave, Urbana, IL 61801 USA;
推荐引用方式 GB/T 7714	Fu, Ting,Kim, Young-Chae,Byun, Sangwon,et al. FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho[J]. MOLECULAR ENDOCRINOLOGY,2016,30(1):92-103.
APA	Fu, Ting.,Kim, Young-Chae.,Byun, Sangwon.,Kim, Dong-Hyun.,Seok, Sunmi.,...&Kemper, Jongsook Kim.(2016).FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho.MOLECULAR ENDOCRINOLOGY,30(1),92-103.
MLA	Fu, Ting,et al."FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho".MOLECULAR ENDOCRINOLOGY 30.1(2016):92-103.