Abstract
Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Caco-2 Cells
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Chenodeoxycholic Acid / pharmacology
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Cholesterol / metabolism*
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Cholesterol, Dietary / administration & dosage
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Hepatocytes / metabolism
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Histone Acetyltransferases
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Humans
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Hydroxysteroid Dehydrogenases*
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Hypolipidemic Agents / metabolism
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Hypolipidemic Agents / pharmacology*
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Ligands
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Liver / metabolism
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Membrane Glycoproteins*
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Mice
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Nuclear Receptor Coactivator 1
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Pregnane X Receptor
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Pregnenediones / metabolism
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Pregnenediones / pharmacology*
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Promoter Regions, Genetic
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Protein Structure, Tertiary
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Steroid / antagonists & inhibitors
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Receptors, Steroid / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation / drug effects
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Transfection
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Tumor Cells, Cultured
Substances
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Carrier Proteins
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Cholesterol, Dietary
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DNA-Binding Proteins
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Hypolipidemic Agents
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Ligands
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Membrane Glycoproteins
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Pregnane X Receptor
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Pregnenediones
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Transcription Factors
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bile acid binding proteins
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nuclear receptor subfamily 0, group B, member 2
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farnesoid X-activated receptor
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Chenodeoxycholic Acid
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DNA
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Cholesterol
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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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Histone Acetyltransferases
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NCOA1 protein, human
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Ncoa1 protein, mouse
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Nuclear Receptor Coactivator 1