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.

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