title: Hepatocyte FRS2α is essential for the endocrine fibroblast growth factor to limit the amplitude of bile acid production induced by prandial activity.
abstract: In addition to being positively regulated by prandial activity, bile acid production is also negatively controlled by the endocrine fibroblast growth factor 19 (FGF19) or the mouse ortholog FGF15 from the ileum that represses hepatic cholesterol 7 α-hydroxylase (Cyp7a1) expression through activating FGF receptor four (FGFR4). However, how these two regulatory mechanisms interplay to control bile acid homeostasis in the body and the downstream pathways by which FGFR4 regulates Cyp7a1 expression are not fully understood. Here we report that hepatocyte FGFR substrate 2α (FRS2α), a scaffold protein essential for canonical FGFRs to activate the ERK and AKT pathways, was required for the regulation of bile acid production by the FGF15/19-FGFR4 signaling axis. This occurred through limiting the extent of increases in Cyp7a1 expression induced by prandial activity. Excess FGFR4 kinase activity reduced the amplitude of the increase whereas a lack of FGFR4 augmented the increase of Cyp7a1 expression in the liver. Ablation of Frs2α alleles in hepatocytes abrogated the regulation of Cyp7a1 expression by FGFR4. Together, the results demonstrate that FRS2α-mediated pathways are essential for the FGF15/FGF19-FGFR4 signaling axis to control bile acid homeostasis.
authors: College of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Cong
authors: C
authors: Wang
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Chaofeng
authors: C
authors: Yang
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Julia Yf
authors: JY
authors: Chang
authors: Xiamen University Affiliated Zhongshang Hospital, China.
authors: Pan
authors: P
authors: You
authors: The Third Affiliated Hospital of Harbin Medical University, China.
authors: Yue
authors: Y
authors: Li
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Chengliu
authors: C
authors: Jin
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Yongde
authors: Y
authors: Luo
authors: College of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Xiaokun
authors: X
authors: Li
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Wallace L
authors: WL
authors: McKeehan
authors: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.
authors: Fen
authors: F
authors: Wang
mesh_terms: D000483:Alleles; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001835:Body Weight; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4