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

Title

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

Creator

Owsley Erika; Chiang John Y L

Publisher

Biochemical and biophysical research communications

Date

2003
2003-04

Description

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.

Subject

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

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

191–195

Issue

1

Volume

304

Citation

Owsley Erika; Chiang John Y L, “Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene.,” NEOMED Bibliography Database, accessed June 16, 2021, https://neomed.omeka.net/items/show/5554.

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