A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.
Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Goodwin
B
B
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Jones
S A
SA
Price
R R
RR
Watson
M A
MA
McKee
D D
DD
Moore
L B
LB
Galardi
C
C
Wilson
J G
JG
Lewis
M C
MC
Roth
M E
ME
Maloney
P R
PR
Willson
T M
TM
Kliewer
S A
SA
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015152:Blotting, Northern; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C082631:NR5A2 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat