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 7alpha-hydroxylase (Cyp 7a1),
sterol 12alpha-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.