Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene.

Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene.

Owsley Erika; Chiang John Y L

Biochemical and biophysical research communications

2003

2003-04

Bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces bile salt export pump (BSEP) but inhibits cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription in the liver. Guggulsterone, a plant sterol that lowers serum cholesterol, has been shown to antagonize FXR activated genes. Transient transfection assay of a human BSEP/luciferase reporter in HepG2 cells transfected with FXR reveals that guggulsterone strongly antagonizes bile acid induction of the BSEP gene. On the other hand, guggulsterone has no effect on FXR inhibition of the CYP7A1 gene, but strongly inhibits the human CYP7A1 gene by activation of pregnane X receptor (PXR). These results suggest that guggulsterone inhibits bile acid secretion from hepatocytes into bile and activates PXR to inhibit bile acid synthesis in the liver. Reduced conversion of cholesterol and bile acid excretion may lead to an increase of hepatic cholesterol and decrease of intestinal cholesterol absorption, and results in lowering serum cholesterol.

Humans; Cell Line; Gene Expression Regulation/drug effects; Pregnane X Receptor; Cholesterol 7-alpha-Hydroxylase/*genetics; ATP-Binding Cassette Transporters/*genetics; Chenodeoxycholic Acid/antagonists & inhibitors; DNA-Binding Proteins/*antagonists & inhibitors/metabolism; Pregnenediones/*pharmacology; Transcription Factors/*antagonists & inhibitors/metabolism; Transcriptional Activation/drug effects; Dose-Response Relationship; Drug; Receptors; ATP Binding Cassette Transporter; Subfamily B; Cytoplasmic and Nuclear/*metabolism; Steroid/*metabolism; Member 11

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