A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

B Goodwin; S A Jones; R R Price; M A Watson; D D McKee; L B Moore; C Galardi; J G Wilson; M C Lewis; M E Roth; P R Maloney; T M Willson; S A Kliewer

doi:10.1016/s1097-2765(00)00051-4

A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

Mol Cell. 2000 Sep;6(3):517-26. doi: 10.1016/s1097-2765(00)00051-4.

Authors

B Goodwin¹, S A Jones, R R Price, M A Watson, D D McKee, L B Moore, C Galardi, J G Wilson, M C Lewis, M E Roth, P R Maloney, T M Willson, S A Kliewer

Affiliation

¹ Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.

PMID: 11030332
DOI: 10.1016/s1097-2765(00)00051-4

Abstract

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.

MeSH terms

Animals
Bile Acids and Salts / biosynthesis*
Blotting, Northern
Cells, Cultured
Cholesterol 7-alpha-Hydroxylase / genetics
Cholesterol 7-alpha-Hydroxylase / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Gene Expression Regulation, Enzymologic / physiology
Hepatocytes / cytology
Hepatocytes / enzymology
Humans
Intracellular Signaling Peptides and Proteins
Male
Promoter Regions, Genetic / physiology
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / metabolism*
RNA, Messenger / analysis
Rats
Rats, Inbred F344
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection

Substances

Bile Acids and Salts
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
NR5A2 protein, human
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Repressor Proteins
Transcription Factors
farnesoid X-activated receptor
Cholesterol 7-alpha-Hydroxylase
PTPN11 protein, human
PTPN6 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases
Ptpn11 protein, rat
Ptpn6 protein, rat