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
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Bile Acids and Salts / chemistry
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Bile Acids and Salts / pharmacology*
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Cell Line
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Chenodeoxycholic Acid / pharmacology
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Cholic Acids / pharmacology
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DNA-Binding Proteins
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Humans
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Kidney / cytology
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Kidney / embryology
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Ligands
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Lithocholic Acid / pharmacology
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Liver X Receptors
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Nuclear Receptor Coactivator 2
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear*
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Receptors, Retinoic Acid / drug effects*
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Receptors, Thyroid Hormone / drug effects*
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / metabolism*
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Recombinant Proteins / drug effects
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Retinoid X Receptors
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Taurodeoxycholic Acid / analogs & derivatives
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Taurodeoxycholic Acid / pharmacology
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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3-oxo-6-hydroxycholanoic acid methyl ester
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Bile Acids and Salts
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Cholic Acids
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DNA-Binding Proteins
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Ligands
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Liver X Receptors
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N,N-dimethyl-3-hydroxy-5-cholenamide
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NR1H2 protein, human
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NR1H3 protein, human
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Nuclear Receptor Coactivator 2
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Recombinant Proteins
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Retinoid X Receptors
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Transcription Factors
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Chenodeoxycholic Acid
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taurohyodeoxycholic acid
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Taurodeoxycholic Acid
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Lithocholic Acid