HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 44, 45462-45469, October 29, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/44/45462    most recent M404744200v2 M404744200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jakel, H. Articles by Fruchart, J.-C. Search for Related Content PubMed PubMed Citation Articles by Jakel, H. Articles by Fruchart, J.-C. Social Bookmarking                      What's this?

The Liver X Receptor Ligand T0901317 Down-regulates APOA5 Gene Expression through Activation of SREBP-1c^*

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

From the Département d'Athérosclérose, UR545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie de Lille, 1 rue du Pr. Calmette BP 245, 59019 Lille Cedex, France, Genfit SA, Loos F-59120, France, and the ^¶Genome Sciences Department and Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, California 94720

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 liver X receptor (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-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 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 that 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 small interfering RNA 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 apolipoprotein AV 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.

Received for publication, April 28, 2004 , and in revised form, July 23, 2004.

^* This work was supported by the Foundation Leducq and in part by the NHLBI National Institutes of Health Programs for Genomic Application Grant HL66681 (to L. A. P.) and National Institutes of Health Grant HL071954A (to L. A. P.) through the U.S. Department of Energy under contract number DE-AC03-76SF00098. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 33-3-20-87-77-88; Fax: 33-3-20-87-73-60; E-mail: Jamila.Fruchart{at}genfit.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, G. U. Schuster, J.-A. Gustafsson, M. D. Basso, and P. Nambi Liver X Receptor (LXR)-beta Regulation in LXR{alpha}-Deficient Mice: Implications for Therapeutic Targeting Mol. Pharmacol., October 1, 2006; 70(4): 1340 - 1349. [Abstract] [Full Text] [PDF]

				M. Guardiola, R. Ferre, J. Salazar, C. Alonso-Villaverde, B. Coll, S. Parra, L. Masana, and J. Ribalta Protease Inhibitor-Associated Dyslipidemia in HIV-Infected Patients Is Strongly Influenced by the APOA5-1131T->C Gene Variation Clin. Chem., October 1, 2006; 52(10): 1914 - 1919. [Abstract] [Full Text] [PDF]

				X. Prieur, F. G. Schaap, H. Coste, and J. C. Rodriguez Hepatocyte Nuclear Factor-4{alpha} Regulates the Human Apolipoprotein AV Gene: Identification of a Novel Response Element and Involvement in the Control by Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1{alpha}, AMP-Activated Protein Kinase, and Mitogen-Activated Protein Kinase Pathway Mol. Endocrinol., December 1, 2005; 19(12): 3107 - 3125. [Abstract] [Full Text] [PDF]

				M. Ishihara, T. Kujiraoka, T. Iwasaki, M. Nagano, M. Takano, J. Ishii, M. Tsuji, H. Ide, I. P. Miller, N. E. Miller, et al. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration J. Lipid Res., September 1, 2005; 46(9): 2015 - 2022. [Abstract] [Full Text] [PDF]

				X. Prieur, T. Huby, H. Coste, F. G. Schaap, M. J. Chapman, and J. C. Rodriguez Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5 J. Biol. Chem., July 29, 2005; 280(30): 27533 - 27543. [Abstract] [Full Text] [PDF]

				A. Genoux, H. Dehondt, A. Helleboid-Chapman, C. Duhem, D. W. Hum, G. Martin, L. A. Pennacchio, B. Staels, J. Fruchart-Najib, and J.-C. Fruchart Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR{alpha} Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1186 - 1192. [Abstract] [Full Text] [PDF]

				M. Nowak, A. Helleboid-Chapman, H. Jakel, G. Martin, D. Duran-Sandoval, B. Staels, E. M. Rubin, L. A. Pennacchio, M.-R. Taskinen, J. Fruchart-Najib, et al. Insulin-Mediated Down-Regulation of Apolipoprotein A5 Gene Expression through the Phosphatidylinositol 3-Kinase Pathway: Role of Upstream Stimulatory Factor Mol. Cell. Biol., February 15, 2005; 25(4): 1537 - 1548. [Abstract] [Full Text] [PDF]