Abstract
Ayurveda, the ancient Indian system of health care and medicine, has a well-organized materia medica in which plants form a dominant part. A key illustration of the exploitation of this knowledge toward the development of a modern drug is the isolation and characterization of two antihyperlipidemic compounds, Z-, and E-guggulsterone from the tree Commiphora mukul, the exudate of which has been traditionally used for mitigating lipid disorders. Here, we demonstrate that Z-guggulsterone and an analog, 80-574 currently in clinical trials, act as antagonists of the bile acid receptor (BAR), a member of the intracellular receptor superfamily. These compounds antagonize the activity of BAR in vitro, and in cell culture systems on promoters and endogenous target genes. In biochemical assays, they are able to displace coactivator peptides from the receptor in a dose-dependent manner. The mechanism by which they act as BAR antagonists is likely through their inability to recruit coactivator proteins, failure to release corepressor proteins from unliganded receptor, and ability to compete with BAR agonists to block coactivator recruitment. Our data suggest these compounds may mediate at least some of their effects via the BAR.
MeSH terms
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Cholesterol 7-alpha-Hydroxylase / drug effects
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Cholesterol 7-alpha-Hydroxylase / genetics
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Hydroxysteroid Dehydrogenases*
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Hypolipidemic Agents / pharmacology*
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Inhibitory Concentration 50
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Isoxazoles / pharmacology
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Ligands
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Liver / drug effects
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Liver / metabolism
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Mediator Complex Subunit 1
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Membrane Glycoproteins*
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Nuclear Proteins / drug effects
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Co-Repressor 1
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Pregnadienes / pharmacology
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Pregnenediones / pharmacology*
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Cytoplasmic and Nuclear / drug effects
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Thyroid Hormone / drug effects
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Receptors, Thyroid Hormone / metabolism
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Repressor Proteins / drug effects
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / drug effects
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Transcription Factors / metabolism
Substances
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3-hydroxy-5,16-pregnadien-20-one
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Carrier Proteins
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DNA-Binding Proteins
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Hypolipidemic Agents
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Isoxazoles
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Ligands
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MED1 protein, human
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Mediator Complex Subunit 1
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Membrane Glycoproteins
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NCOR1 protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Pregnadienes
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Pregnenediones
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Receptors, Cytoplasmic and Nuclear
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Receptors, Thyroid Hormone
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Repressor Proteins
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Transcription Factors
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bile acid binding proteins
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farnesoid X-activated receptor
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pregna-4,17-diene-3,16-dione
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Hydroxysteroid Dehydrogenases
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AKR1C2 protein, human
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Cholesterol 7-alpha-Hydroxylase
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GW 4064