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A more recent version of this article appeared on October 29, 2004 Originally published In Press as doi:10.1074/jbc.M404744200 on September 7, 2004
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Papers In Press, published online ahead of print August 17, 2004
J. Biol. Chem, 10.1074/jbc.M404744200
Submitted on April 28, 2004
Revised on August 17, 2004
Accepted on August 17, 2004

The LXR ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c

Heidelinde Jakel, Maxime Nowak, Emanuelle Moitrot, Hélène Dehondt, Dean Hum, Len A. Penacchio, Jamila Fruchart-Najib, and Jean-Charles Fruchart

Département d'Athérosclérose, Institut Pasteur, Lille, Lille 59019

Corresponding Author: heidelinde.jakel{at}pasteur-lille.fr

Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the LXR ligand mediated effect on plasma triglyceride levels. Following treatment with the LXR ligand T0901317, we found that APOA5 mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-RXR co-transfection, prompted us to explore the possible involvement of the known LXR target gene SREBP-1c. In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5 promoter activity in a dose dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements which were able to bind specifically SREBP-1c in gel shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through siRNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease of APOA5 mRNA in liver tissue and circulating apoAV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands, and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.


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