Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs.
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.
Ben May Institute for Cancer Research, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
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D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002793:Cholic Acids / Q000494:pharmacology; D004268:DNA-Binding Proteins; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008024:Ligands; D008095:Lithocholic Acid / Q000494:pharmacology; D000071518:Liver X Receptors; D051958:Nuclear Receptor Coactivator 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D013657:Taurodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
C413891:3-oxo-6-hydroxycholanoic acid methyl ester; D001647:Bile Acids and Salts; D002793:Cholic Acids; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C413890:N,N-dimethyl-3-hydroxy-5-cholenamide; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D051958:Nuclear Receptor Coactivator 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002635:Chenodeoxycholic Acid; C083510:taurohyodeoxycholic acid; D013657:Taurodeoxycholic Acid; D008095:Lithocholic Acid