Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expression
- Resource Type
- Authors
- John Y.L. Chiang; Kwang-Hoon Song; Stephen C. Strom; Erika Owsley; Tiangang Li
- Source
- Hepatology. 49:297-305
- Subject
- Carcinoma, Hepatocellular
medicine.drug_class
Gene Expression
Receptors, Cytoplasmic and Nuclear
Biology
Chenodeoxycholic Acid
Cholesterol 7 alpha-hydroxylase
Article
chemistry.chemical_compound
Cell Line, Tumor
Chenodeoxycholic acid
Nitriles
Butadienes
medicine
Humans
Receptor, Fibroblast Growth Factor, Type 4
Cholesterol 7-alpha-Hydroxylase
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Hepatology
Bile acid
FGF15
FGF19
Isoxazoles
G protein-coupled bile acid receptor
Cell biology
DNA-Binding Proteins
Fibroblast Growth Factors
chemistry
Biochemistry
Hepatocytes
Small heterodimer partner
Farnesoid X receptor
Signal Transduction
Transcription Factors
- Language
- ISSN
- 0270-9139
Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism.The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers.