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Papers In Press, published online ahead of print September 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400221-JLR200
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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.
Revised on August 13, 2004
Accepted on August 16, 2004
Farnesoid X receptor represses hepatic lipase gene expression
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