Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.
The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.
Holt
Jason A
JA
Nuclear Receptor Discovery Research, High Throughput Biology, Gene Interference, Transgenics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA .
Luo
Guizhen
G
Billin
Andrew N
AN
Bisi
John
J
McNeill
Y Yvette
YY
Kozarsky
Karen F
KF
Donahee
Mary
M
Wang
Da Yuan
DY
Mansfield
Traci A
TA
Kliewer
Steven A
SA
Goodwin
Bryan
B
Jones
Stacey A
SA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002460:Cell Line; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004794:Enzyme Repression; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D000873:Anthracenes; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D005346:Fibroblast Growth Factors; D007555:Isoxazoles; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C432165:pyrazolanthrone; C412815:GW 4064