The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor.
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.
Wu
Jun
J
Department of Biotechnology, Pharmacia Corp., St. Louis, Missouri 63198, USA.
Xia
Chunsheng
C
Meier
Jannika
J
Li
Suzhen
S
Hu
Xiao
X
Lala
Deepak S
DS
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D056913:Mediator Complex Subunit 1; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D011245:Pregnadienes / Q000494:pharmacology; D011282:Pregnenediones / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D002352:Carrier Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D006913:Hydroxysteroid Dehydrogenases; D000960:Hypolipidemic Agents; D007555:Isoxazoles; D008024:Ligands; D056913:Mediator Complex Subunit 1; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011245:Pregnadienes; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C470852:3-hydroxy-5,16-pregnadien-20-one; C538855:MED1 protein, human; C539127:NCOR1 protein, human; C037643:bile acid binding proteins; C023617:pregna-4,17-diene-3,16-dione; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C412815:GW 4064