Nl. Urizar et al., The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression, J BIOL CHEM, 275(50), 2000, pp. 39313-39317
Bile acids facilitate the absorption of dietary lipids and fat-soluble vita
mins and are physiological ligands for the farnesoid X-activated receptor (
FXR), a member of the nuclear hormone receptor superfamily, FXR functions a
s a heterodimer with the retinoid X receptor and in the presence of ligand,
the heterodimer binds to specific DNA sequences in the promoters of target
genes to regulate gene transcription. Phospholipid transfer protein (PLTP)
has been identified as a possible target gene for FXR because the human pr
omoter contains a potential FXR response element, an inverted repeat in whi
ch consensus receptor-binding hexamers are separated by one nucleotide (inv
erted repeat-1). PLTP is essential in the transfer of very low density lipo
protein phospholipids into high density lipoprotein (Jiang, X, C., Bruce, C
., Mar, J., Lin, M., Ji, Y., Francone, O. L., and Tall, A. R. (1999) J. Cli
n. Invest. 103, 907-914), Here we report the regulation of PLTP gene expres
sion by FXR and bile acids. In CV-1 cells, cotransfection of FXR and the re
tinoid X receptor resulted in bile acid-dependent transactivation of a luci
ferase reporter construct containing the human PLTP promoter. Mutation anal
ysis demonstrated that the inverted repeat-1 (IR-l) in the PLTP promoter is
required for this transactivation. Finally, we demonstrate that bile acids
are able to regulate PLTP gene expression in vivo. Mice fed a chow diet su
pplemented with bile acid showed increased hepatic PLTP mRNA levels. These
results suggest that FXR may play a role in high density lipoprotein metabo
lism via the regulation of PLTP gene expression.