Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis

doi:10.1016/j.cmet.2014.05.020

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	Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis
	Li, Shuangwei 3; Hsu, Diane D. F.3; Li, Bing 2; Luo, Xiaolin 3; Alderson, Nazilla 3; Qiao, Liping 1; Ma, Lina 7; Zhu, Helen H.3; He, Zhao 3; Suino-Powell, Kelly 6
刊名	CELL METABOLISM
	2014-08-05
卷号	20 期号:2 页码:320-332
ISSN号	1550-4131
DOI	10.1016/j.cmet.2014.05.020
文献子类	Article
英文摘要	Bile acid (BA) biosynthesis is tightly controlled by intrahepatic negative feedback signaling elicited by BA binding to farnesoid X receptor (FXR) and also by enterohepatic communication involving ileal BA reabsorption and FGF15/19 secretion. However, how these pathways are coordinated is poorly understood. Weshow here that nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates the intrahepatic and enterohepatic signals for repression of BA synthesis. Ablating Shp2 in hepatocytes suppressed signal relay from FGFR4, receptor for FGF15/19, and attenuated BA activation of FXR signaling, resulting in elevation of systemic BA levels and chronic hepatobiliary disorders in mice. Acting immediately downstream of FGFR4, Shp2 associates with FRS2a and promotes the receptor activation and signal relay to several pathways. These results elucidate a molecular mechanism for the control of BA homeostasis by Shp2 through the orchestration of multiple signals in hepatocytes.
资助项目	NIH[R01HL096125] ; NIH[R01CA176012] ; NIH[R01DK066202] ; NIH[R01HD069634] ; NIH[P20GM103549] ; ADA grant[1-13-BS-048]
WOS关键词	FARNESOID-X RECEPTOR ; SMALL HETERODIMER PARTNER ; NUCLEAR RECEPTOR ; FEEDBACK-REGULATION ; LIVER-REGENERATION ; LIPID HOMEOSTASIS ; SALT ABSORPTION ; GENE-EXPRESSION ; MICE ; METABOLISM
WOS研究方向	Cell Biology ; Endocrinology & Metabolism
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000341402500017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276948]
专题	药物靶标结构与功能中心
通讯作者	Feng, Gen-Sheng
作者单位	1.Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA; 2.Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA; 3.Univ Calif San Diego, Dept Pathol, Div Biol Sci, La Jolla, CA 92093 USA; 4.Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China; 6.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 7.Salk Inst Biol Sci, Mol Neurosci Lab, San Diego, CA 92186 USA;
推荐引用方式 GB/T 7714	Li, Shuangwei,Hsu, Diane D. F.,Li, Bing,et al. Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis[J]. CELL METABOLISM,2014,20(2):320-332.
APA	Li, Shuangwei.,Hsu, Diane D. F..,Li, Bing.,Luo, Xiaolin.,Alderson, Nazilla.,...&Feng, Gen-Sheng.(2014).Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis.CELL METABOLISM,20(2),320-332.
MLA	Li, Shuangwei,et al."Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis".CELL METABOLISM 20.2(2014):320-332.