Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs

Steroids. 2000 Aug;65(8):423-7. doi: 10.1016/s0039-128x(00)00127-6.

Abstract

We have found that certain natural 6alpha-hydroxylated bile acids are receptor-specific activators of nuclear liver X receptor alpha (LXRalpha) (NR1H3), a nuclear receptor regulating the expression of the cholesterol 7alpha-hydroxylase gene, coding for the rate-limiting enzyme in the major pathway of bile acid synthesis. The LXR homolog, ubiquitous nuclear receptor (UR/LXRbeta) (NR1H2), was also activated by these bile acids, but at higher concentrations than for LXRalpha. Synthetic 6alpha-hydroxylated bile acid analogs were synthesized with LXRalpha-selective agonistic activity, with potential to modulate cholesterol catabolism in hypercholesterolemia.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bile Acids and Salts / chemistry
  • Bile Acids and Salts / pharmacology*
  • Cell Line
  • Chenodeoxycholic Acid / pharmacology
  • Cholic Acids / pharmacology
  • DNA-Binding Proteins
  • Humans
  • Kidney / cytology
  • Kidney / embryology
  • Ligands
  • Lithocholic Acid / pharmacology
  • Liver X Receptors
  • Nuclear Receptor Coactivator 2
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear*
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Thyroid Hormone / drug effects*
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism*
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Retinoid X Receptors
  • Taurodeoxycholic Acid / analogs & derivatives
  • Taurodeoxycholic Acid / pharmacology
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • 3-oxo-6-hydroxycholanoic acid methyl ester
  • Bile Acids and Salts
  • Cholic Acids
  • DNA-Binding Proteins
  • Ligands
  • Liver X Receptors
  • N,N-dimethyl-3-hydroxy-5-cholenamide
  • NR1H2 protein, human
  • NR1H3 protein, human
  • Nuclear Receptor Coactivator 2
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Recombinant Proteins
  • Retinoid X Receptors
  • Transcription Factors
  • Chenodeoxycholic Acid
  • taurohyodeoxycholic acid
  • Taurodeoxycholic Acid
  • Lithocholic Acid