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J. Biol. Chem., Vol. 277, Issue 35, 31441-31447, August 30, 2002
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,,,
From the Department of Atherosclerosis and Endocrinology and the
Bile salt export pump (BSEP) is a major bile acid
transporter in the liver. Mutations in BSEP result in progressive
intrahepatic cholestasis, a severe liver disease that impairs bile flow
and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and
such inhibition and down-regulation may result in bile acid retention
and intrahepatic cholestasis. In this study, we quantitatively analyzed
the regulation of BSEP expression by FXR ligands in primary human
hepatocytes and HepG2 cells. We demonstrate that BSEP expression is
dramatically regulated by ligands of the nuclear receptor farnesoid X
receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the
BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064,
lithocholate (LCA), a hydrophobic bile acid and a potent inducer of
cholestasis, strongly decreased BSEP expression. Previous studies did
not identify LCA as an FXR antagonist ligand in cells, but we
show here that LCA is an FXR antagonist with partial agonist activity
in cells. In an in vitro co-activator association assay,
LCA decreased CDCA- and GW4064-induced FXR activation with an
IC50 of 1 µM. In HepG2 cells, LCA also
effectively antagonized GW4064-enhanced FXR transactivation. These data
suggest that the toxic and cholestatic effect of LCA in animals may
result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP
gene expression and that FXR ligands may be potential therapeutic drugs
for intrahepatic cholestasis.
Department of Medicinal Chemistry, Merck Research
Laboratories, Rahway, New Jersey 07065
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