J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M400221-JLR200 on September 1, 2004

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Journal of Lipid Research, Vol. 45, 2110-2115, November 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Farnesoid X receptor represses hepatic lipase gene expression

Audrey Sirvent*,{dagger}, Adrie J. M. Verhoeven§, Hans Jansen§, Vladimir Kosykh**, Raphaël J. Darteil*, Dean W. Hum*, Jean-Charles Fruchart{dagger} and Bart Staels1,{dagger}

* GENFIT, Parc Eurasanté, Loos, France
{dagger} U545 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, and the Faculté de Pharmacie, Université de Lille II, Lille, France
§ Department of Clinical Chemistry, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands
** Cardiology Research Center, Academy of Medical Sciences, Moscow, Russia

1 To whom correspondence should be addressed. e-mail: bart.staels{at}pasteur-lille.fr

The farnesoid X receptor (FXR) is a nuclear receptor that regulates gene expression in response to bile acids (BAs). FXR plays a central role in BA, cholesterol, and lipoprotein metabolism. Here, we identify HL, an enzyme involved in the metabolism of remnant and high density lipoproteins, as a novel FXR-regulated gene. The natural FXR ligand, chenodeoxycholic acid (CDCA), downregulates HL gene expression in a dose- and time-dependent manner in human hepatoma HepG2 cells. The nonsteroidal synthetic FXR agonist GW4064 also decreases HL mRNA levels in HepG2 cells and in primary human hepatocytes. Moreover, the decrease of HL mRNA levels after treatment with FXR agonists was associated with a significant decrease in secreted enzymatic activity. In addition, FXR-specific gene silencing using small interfering RNAs demonstrated that CDCA- and GW4064-mediated downregulation of HL transcript levels occurs via an FXR-dependent mechanism. Finally, using transient transfection experiments, it is shown that FXR represses transcriptional activity of a reporter driven by the –698/+13 bp human HL promoter.

Taken together, these results identify HL as a new FXR-regulated gene in human liver cells. In view of the role of HL in plasma lipoprotein metabolism, our results further emphasize the central role of FXR in lipid homeostasis.

Abbreviations: apoA-I, apolipoprotein A-I; BA, bile acid; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; FXR, farnesoid X receptor; FXRE, FXR response element; IR1, inverted repeat spaced by one nucleotide; SHP, small heterodimer partner; siRNA, small interfering RNA

Supplementary key words hepatocytes • small interfering ribonucleic acids • lipid metabolism


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