title: Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.
abstract: 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. We show 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 FRS2α 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.
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Shuangwei
authors: S
authors: Li
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Diane D F
authors: DD
authors: Hsu
authors: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Bing
authors: B
authors: Li
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Xiaolin
authors: X
authors: Luo
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Nazilla
authors: N
authors: Alderson
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA.
authors: Liping
authors: L
authors: Qiao
authors: Molecular Neuroscience Laboratory, The Salk Institute for Biological Sciences, La Jolla, CA 92186, USA.
authors: Lina
authors: L
authors: Ma
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Helen H
authors: HH
authors: Zhu
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Zhao
authors: Z
authors: He
authors: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA.
authors: Kelly
authors: K
authors: Suino-Powell
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Kaihong
authors: K
authors: Ji
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA.
authors: Jiefu
authors: J
authors: Li
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0983, USA.
authors: Jianhua
authors: J
authors: Shao
authors: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA; VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: H Eric
authors: HE
authors: Xu
authors: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Tiangang
authors: T
authors: Li
authors: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864, USA. Electronic address: gfeng@ucsd.edu.
authors: Gen-Sheng
authors: GS
authors: Feng
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001652:Bile Ducts / Q000293:injuries; D002460:Cell Line; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; C488187:FRS2alpha protein, mouse; C484726:Fgf17 protein, mouse; D008565:Membrane Proteins; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse