The Farnesoid X-activated Receptor Mediates Bile Acid Activation of Phospholipid Transfer Protein Gene Expression

Nancy L Urizar,Dennis H Dowhan,David D Moore

doi:10.1074/jbc.m007998200

Nancy L Urizar, Dennis H Dowhan + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m007998200

Copy DOI

Abstract

Bile acids facilitate the absorption of dietary lipids and fat-soluble vitamins and are physiological ligands for the farnesoid X-activated receptor (FXR), a member of the nuclear hormone receptor superfamily. FXR functions as 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 promoter contains a potential FXR response element, an inverted repeat in which consensus receptor-binding hexamers are separated by one nucleotide (inverted repeat-1). PLTP is essential in the transfer of very low density lipoprotein 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. Clin. Invest. 103, 907-914). Here we report the regulation of PLTP gene expression by FXR and bile acids. In CV-1 cells, cotransfection of FXR and the retinoid X receptor resulted in bile acid-dependent transactivation of a luciferase reporter construct containing the human PLTP promoter. Mutation analysis demonstrated that the inverted repeat-1 (IR-1) 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 supplemented with bile acid showed increased hepatic PLTP mRNA levels. These results suggest that FXR may play a role in high density lipoprotein metabolism via the regulation of PLTP gene expression.

Highlights

The major metabolic pathway for the elimination of cholesterol is its conversion into bile acids in the liver
Since farnesoid X-activated receptor (FXR) and Phospholipid transfer protein (PLTP) are coexpressed in the liver, where bile acids are present at concentrations required to activate FXR, and because the human PLTP promoter has a potential FXR response element, we decided to study the role of FXR and its ligand chenodeoxycholic acid (CDCA) in the regulation of PLTP gene expression
Monkey kidney CV-1 cells were cotransfected with FXR and retinoid X receptor (RXR)␣ expression plasmids plus the PLTP940 reporter construct in the absence of ligand or in the presence of 100 ␮M CDCA and/or 1 ␮M 9-cis-retinoic acid, an RXR␣ ligand (Fig. 1A)

Summary

Introduction

The major metabolic pathway for the elimination of cholesterol is its conversion into bile acids in the liver. We report the regulation of PLTP gene expression by FXR and bile acids. In CV-1 cells, cotransfection of FXR and the retinoid X receptor resulted in bile acid-dependent transactivation of a luciferase reporter construct containing the human PLTP promoter.

Results

Conclusion