Cholic acid mediates negative feedback regulation of bile acid synthesis in mice.
Cholesterol is converted into dozens of primary and secondary bile acids through pathways subject to negative feedback regulation mediated by the nuclear receptor farnesoid X receptor (FXR) and other effectors. Disruption of the sterol 12alpha-hydroxylase gene (Cyp8b1) in mice prevents the synthesis of cholate, a primary bile acid, and its metabolites. Feedback regulation of the rate-limiting biosynthetic enzyme cholesterol 7alpha-hydroxylase (CYP7A1) is lost in Cyp8b1(-/-) mice, causing expansion of the bile acid pool and alterations in cholesterol metabolism. Expression of other FXR target genes is unaltered in these mice. Cholate restores CYP7A1 regulation in vivo and in vitro. The results implicate cholate as an important negative regulator of bile acid synthesis and provide preliminary evidence for ligand-specific gene activation by a nuclear receptor.
Li-Hawkins
Jia
J
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046, USA.
Gåfvels
Mats
M
Olin
Maria
M
Lund
Erik G
EG
Andersson
Ulla
U
Schuster
Gertrud
G
Björkhem
Ingemar
I
Russell
David W
DW
Eggertsen
Gosta
G
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005246:Feedback; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2