A natural product that lowers cholesterol as an antagonist ligand for FXR.
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.
Urizar
Nancy L
NL
Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Liverman
Amy B
AB
Dodds
D'Nette T
DT
Silva
Frank Valentin
FV
Ordentlich
Peter
P
Yan
Yingzhuo
Y
Gonzalez
Frank J
FJ
Heyman
Richard A
RA
Mangelsdorf
David J
DJ
Moore
David D
DD
D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D000077297:Pregnane X Receptor; D011282:Pregnenediones / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D002352:Carrier Proteins; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D002791:Cholesterol, Dietary; D004247:DNA; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006913:Hydroxysteroid Dehydrogenases; D000960:Hypolipidemic Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D056920:Nuclear Receptor Coactivator 1; D000077297:Pregnane X Receptor; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C037643:bile acid binding proteins; C099713:nuclear receptor subfamily 0, group B, member 2; C023617:pregna-4,17-diene-3,16-dione; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse