J. Lipid Res.
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A more recent version of this article appeared on November 1, 2004

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J. Lipid Res., doi:10.1194/jlr.M400221-JLR200
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Submitted on June 14, 2004
Revised on August 13, 2004
Accepted on August 16, 2004

Farnesoid X receptor represses hepatic lipase gene expression

Audrey Sirvent, Adrie J. M. Verhoeven, Hans Jansen, Vladimir Kosykh, Raphaël J. Darteil, Dean W. Hum, Jean-Charles Fruchart, and Bart Staels

Parc Eurasante, GENFIT, Loos Les Lille, Loos Les Lille 59120

Corresponding Author: audrey.sirvent{at}genfit.com

The Farnesoid X Receptor (FXR) is a nuclear receptor that regulates gene expression in response to bile acids. FXR plays a central role in bile acid, cholesterol and lipoprotein metabolism. Here we identify hepatic lipase (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), down-regulates HL gene expression in a dose- and time-dependant manner in human hepatoma HepG2 cells. The non-steroidal 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 RNA (siRNA) demonstrated that CDCA- and GW4064-mediated down-regulation of HL transcript levels occurs via an FXR-dependant mechanism. Finally, using transient transfection experiments it is shown that FXR represses transcriptional activity of a reporter driven by the –698bp/+13bp 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.


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