Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis.
The in vivo role of the nuclear receptor SHP in feedback regulation of bile acid synthesis was examined. Loss of SHP in mice caused abnormal accumulation and increased synthesis of bile acids due to derepression of rate-limiting CYP7A1 and CYP8B1 hydroxylase enzymes in the biosynthetic pathway. Dietary bile acids induced liver damage and restored feedback regulation. A synthetic agonist of the nuclear receptor FXR was not hepatotoxic and had no regulatory effects. Reduction of the bile acid pool with cholestyramine enhanced CYP7A1 and CYP8B1 expression. We conclude that input from three negative regulatory pathways controls bile acid synthesis. One is mediated by SHP, and two are SHP independent and invoked by liver damage and changes in bile acid pool size.
Kerr
Thomas A
TA
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Saeki
Shigeru
S
Schneider
Manfred
M
Schaefer
Karen
K
Berdy
Sara
S
Redder
Thadd
T
Shan
Bei
B
Russell
David W
DW
Schwarz
Margrit
M
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000097:blood; D002792:Cholestyramine Resin / Q000008:administration & dosage / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005246:Feedback; D005786:Gene Expression Regulation; D007555:Isoxazoles / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D016601:RNA-Binding Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013250:Steroid Hydroxylases / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D039221:mRNA Cleavage and Polyadenylation Factors; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002792:Cholestyramine Resin; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D014157:Transcription Factors; D014280:Triglycerides; D039221:mRNA Cleavage and Polyadenylation Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C412815:GW 4064