J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500378-JLR200 on November 3, 2005

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Journal of Lipid Research, Vol. 47, 384-392, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids

Diana M. Shih1,*, Heidi R. Kast-Woelbern{dagger},2, Jack Wong*, Yu-Rong Xia*, Peter A. Edwards{dagger} and Aldons J. Lusis*,§

* Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095
{dagger} Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095
§ Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095

Published, JLR Papers in Press, November 3, 2005.

2 Present address for H. R. Kast-Woelbern: Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, CA 92121.

1 To whom correspondence should be addressed. e-mail: dshih{at}mednet.ucla.edu

Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal –230 to –96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.

Supplementary key words gene regulation • high density lipoprotein • atherosclerosis • mouse • c-Jun N-terminal kinase • farnesoid X receptor • fibroblast growth factor-19

Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7{alpha}-hydroxylase; FGF-19, fibroblast growth factor-19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; HNF-4, hepatocyte nuclear factor 4; JNK, c-Jun N-terminal kinase; PON1, paraoxonase-1; RXR, retinoid X receptor; SHP, small heterodimer partner; SREBP-2, sterol-regulatory element binding protein-2


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