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J. Biol. Chem., Vol. 278, Issue 12, 10214-10220, March 21, 2003
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From the Department of Atherosclerosis and Endocrinology,
§ Department of Medicinal Chemistry, Merck Research
Laboratories, Rahway, New Jersey 07065 and the ¶ Centro de
Investigacion Basica, Merck Sharp and Dohme de Espana, S.A., Josefa
Valcarcel 38, 28027 Madrid, Spain
Guggulipid is an extract of the guggul tree
Commiphora mukul and has been widely used to treat
hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the
active agent in this extract. Recent studies have shown that GS can act
as an antagonist ligand for farnesoid X receptor (FXR) and decrease
expression of bile acid-activated genes. Here we show that GS, although
an FXR antagonist in coactivator association assays, enhances FXR
agonist-induced transcription of bile salt export pump
(BSEP), a major hepatic bile acid transporter. In
HepG2 cells, in the presence of an FXR agonist such as
chenodeoxycholate or GW4064, GS enhanced endogenous BSEP expression with a maximum induction of 400-500% that
induced by an FXR agonist alone. This enhancement was also readily
observed in FXR-dependent BSEP promoter
activation using a luciferase reporter construct. In addition, GS alone
slightly increased BSEP promoter activation in the absence
of an FXR agonist. Consistent with the results in HepG2, guggulipid
treatment in Fisher rats increased BSEP mRNA.
Interestingly, in these animals expression of the orphan nuclear
receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other
FXR targets including cholesterol 7
Guggulsterone Is a Farnesoid X Receptor Antagonist in
Coactivator Association Assays but Acts to Enhance Transcription of
Bile Salt Export Pump*
,
-hydroxylase (Cyp
7a1), sterol 12-hydroxylase (Cyp 8b1), and the
intestinal bile acid-binding protein (I-BABP), remained
unchanged. Thus, we propose that GS is a selective
bile acid receptor
modulator that regulates expression of a subset of FXR
targets. Guggulipid treatment in rats lowered serum triglyceride and
raised serum high density lipoprotein levels. Taken together, these
data suggest that guggulsterone defines a novel class of FXR ligands
characterized by antagonist activities in coactivator association
assays but with the ability to enhance the action of agonists on
BSEP expression in vivo.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Atherosclerosis and Endocrinology, Merck Research Laboratories, 126 E. Lincoln Ave., P. O. Box 2000, RY80W-107, Rahway, NJ 07065. Tel.: 732-594-6369; Fax: 732-594-7926; E-mail: jisong_cui@merck.com.
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