This Article Full Text Full Text (PDF) 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gervois, P. Articles by Staels, B. Search for Related Content PubMed PubMed Citation Articles by Gervois, P. Articles by Staels, B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Fibrates Increase Human REV-ERB Expression in Liver via a Novel Peroxisome Proliferator-Activated Receptor Response Element

U.325 INSERM Département d’Athérosclérose (P.G., A.F., G.D., J.-C.F., J.N., B.S.) Institut Pasteur de Lille and The Faculté de Pharmacie Université de Lille II 59019 Lille, France
Endocrino’s Group (S.C.-D.) CNRS UMR 319 Institut de Biologie de Lille 59019 Lille, France
Cardiology Research Complex (V.K.) 721552 Moscow, Russia
E.N.S. (V.L.) 69364 Lyon cedex 07, France

Fibrates are widely used hypolipidemic drugs that act by modulating the expression of genes involved in lipid and lipoprotein metabolism. Whereas the activation of gene transcription by fibrates occurs via the nuclear receptor peroxisome proliferator-activated receptor- (PPAR) interacting with response elements consisting of a direct repeat of the AGGTCA motif spaced by one nucleotide (DR1), the mechanisms of negative gene regulation by fibrates and PPAR are largely unknown. In the present study, we demonstrate that fibrates induce the expression of the nuclear receptor Rev-erb, a negative regulator of gene transcription. Fibrates increase Rev-erb mRNA levels both in primary human hepatocytes and in HepG2 hepatoblastoma cells. In HepG2 cells, fibrates furthermore induce Rev-erb protein synthesis rates. Transfection studies with reporter constructs driven by the human Rev-erb promoter revealed that fibrates induce Rev-erb expression at the transcriptional level via PPAR. Site-directed mutagenesis experiments identified a PPAR response element that coincides with the previously identified Rev-erb negative autoregulatory Rev-DR2 element. Electromobility shift assay experiments indicated that PPAR binds as heterodimer with 9-cis-retinoic acid receptor to a subset of DR2 elements 5' flanked by an A/T-rich sequence such as in the Rev-DR2. PPAR and Rev-erb bind with similar affinities to the Rev-DR2 site. In conclusion, these data demonstrate human Rev-erb as a PPAR target gene and identify a subset of DR2 sites as novel PPAR response elements. Finally, the PPAR and Rev-erb signaling pathways cross-talk through competition for binding to those response elements.

This article has been cited by other articles:

				D. Mymin, T. Dembinski, and M. H. Friesen Iatrogenic Severe Depression of High-Density Lipoprotein Cholesterol J. Clin. Pharmacol., July 1, 2009; 49(7): 865 - 871. [Abstract] [Full Text] [PDF]

				J. Rambaud, G. Triqueneaux, I. Masse, B. Staels, V. Laudet, and G. Benoit Rev-erb{alpha}2 mRNA Encodes a Stable Protein with a Potential Role in Circadian Clock Regulation Mol. Endocrinol., May 1, 2009; 23(5): 630 - 639. [Abstract] [Full Text] [PDF]

				C. Fontaine, E. Rigamonti, B. Pourcet, H. Duez, C. Duhem, J.-C. Fruchart, G. Chinetti-Gbaguidi, and B. Staels The Nuclear Receptor Rev-erb{alpha} Is a Liver X Receptor (LXR) Target Gene Driving a Negative Feedback Loop on Select LXR-Induced Pathways in Human Macrophages Mol. Endocrinol., August 1, 2008; 22(8): 1797 - 1811. [Abstract] [Full Text] [PDF]

				T. P. Burris Nuclear Hormone Receptors for Heme: REV-ERB{alpha} and REV-ERB{beta} Are Ligand-Regulated Components of the Mammalian Clock Mol. Endocrinol., July 1, 2008; 22(7): 1509 - 1520. [Abstract] [Full Text] [PDF]

				H. Duez and B. Staels The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism Diabetes and Vascular Disease Research, June 1, 2008; 5(2): 82 - 88. [Abstract] [PDF]

				R. M. Mansouri, E. Bauge, B. Staels, and P. Gervois Systemic and Distal Repercussions of Liver-Specific Peroxisome Proliferator-Activated Receptor-{alpha} Control of the Acute-Phase Response Endocrinology, June 1, 2008; 149(6): 3215 - 3223. [Abstract] [Full Text] [PDF]

				T. Kakizawa, S.-i. Nishio, G. Triqueneaux, S. Bertrand, J. Rambaud, and V. Laudet Two differentially active alternative promoters control the expression of the zebrafish orphan nuclear receptor gene Rev-erb{alpha} J. Mol. Endocrinol., May 1, 2007; 38(5): 555 - 568. [Abstract] [Full Text] [PDF]

				X. Yang, K. A. Lamia, and R. M. Evans Nuclear Receptors, Metabolism, and the Circadian Clock Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 387 - 394. [Abstract] [PDF]

				L. Canaple, J. Rambaud, O. Dkhissi-Benyahya, B. Rayet, N. S. Tan, L. Michalik, F. Delaunay, W. Wahli, and V. Laudet Reciprocal Regulation of Brain and Muscle Arnt-Like Protein 1 and Peroxisome Proliferator-Activated Receptor {alpha} Defines a Novel Positive Feedback Loop in the Rodent Liver Circadian Clock Mol. Endocrinol., August 1, 2006; 20(8): 1715 - 1727. [Abstract] [Full Text] [PDF]

				A. Zambon, P. Gervois, P. Pauletto, J.-C. Fruchart, and B. Staels Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR-{alpha} Activators: Clinical and Experimental Evidence Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 977 - 986. [Abstract] [Full Text] [PDF]

				G. Triqueneaux, S. Thenot, T. Kakizawa, M. P Antoch, R. Safi, J. S Takahashi, F. Delaunay, and V. Laudet The orphan receptor Rev-erb{alpha} gene is a target of the circadian clock pacemaker J. Mol. Endocrinol., December 1, 2004; 33(3): 585 - 608. [Abstract] [Full Text] [PDF]

				C. Fontaine, G. Dubois, Y. Duguay, T. Helledie, N. Vu-Dac, P. Gervois, F. Soncin, S. Mandrup, J.-C. Fruchart, J. Fruchart-Najib, et al. The Orphan Nuclear Receptor Rev-Erb{alpha} Is a Peroxisome Proliferator-activated Receptor (PPAR) {gamma} Target Gene and Promotes PPAR{gamma}-induced Adipocyte Differentiation J. Biol. Chem., September 26, 2003; 278(39): 37672 - 37680. [Abstract] [Full Text] [PDF]

				K. Hellemans, K. Rombouts, E. Quartier, A. S. Dittie, A. Knorr, L. Michalik, V. Rogiers, F. Schuit, W. Wahli, and A. Geerts PPAR{beta} regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation J. Lipid Res., February 1, 2003; 44(2): 280 - 295. [Abstract] [Full Text] [PDF]

				E. Raspe, G. Mautino, C. Duval, C. Fontaine, H. Duez, O. Barbier, D. Monte, J. Fruchart, J.-C. Fruchart, and B. Staels Transcriptional Regulation of Human Rev-erbalpha Gene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor alpha J. Biol. Chem., December 13, 2002; 277(51): 49275 - 49281. [Abstract] [Full Text] [PDF]

				E. Raspe, H. Duez, A. Mansen, C. Fontaine, C. Fievet, J.-C. Fruchart, B. Vennstrom, and B. Staels Identification of Rev-erb{alpha} as a physiological repressor of apoC-III gene transcription J. Lipid Res., December 1, 2002; 43(12): 2172 - 2179. [Abstract] [Full Text] [PDF]

				P. Delerive, W. W. Chin, and C. S. Suen Identification of Reverbalpha as a Novel RORalpha Target Gene J. Biol. Chem., September 13, 2002; 277(38): 35013 - 35018. [Abstract] [Full Text] [PDF]

				D. Jung, M. Fried, and G. A. Kullak-Ublick Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor alpha J. Biol. Chem., August 16, 2002; 277(34): 30559 - 30566. [Abstract] [Full Text] [PDF]

				H. Coste and J. C. Rodriguez Orphan Nuclear Hormone Receptor Rev-erbalpha Regulates the Human Apolipoprotein CIII Promoter J. Biol. Chem., July 19, 2002; 277(30): 27120 - 27129. [Abstract] [Full Text] [PDF]

				S. M. Post, H. Duez, P. P. Gervois, B. Staels, F. Kuipers, and H. M.G. Princen Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator-Activated Receptor-{alpha}-Mediated Downregulation of Cholesterol 7{alpha}-Hydroxylase and Sterol 27-Hydroxylase Expression Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1840 - 1845. [Abstract] [Full Text] [PDF]

				R. T. Miller, L. A. Scappino, S. M. Long, and J. C. Corton Role of Thyroid Hormones in Hepatic Effects of Peroxisome Proliferators Toxicol Pathol, January 1, 2001; 29(1): 149 - 155. [Abstract] [PDF]

				I. P. Torra, V. Tsibulsky, F. Delaunay, R. Saladin, V. Laudet, J.-C. Fruchart, V. Kosykh, and B. Staels Circadian and Glucocorticoid Regulation of Rev-erb{alpha} Expression in Liver Endocrinology, October 1, 2000; 141(10): 3799 - 3806. [Abstract] [Full Text] [PDF]

				B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]

				V. Giguère Orphan Nuclear Receptors: From Gene to Function Endocr. Rev., October 1, 1999; 20(5): 689 - 725. [Abstract] [Full Text]

				A. Kassam, J. P. Capone, and R. A. Rachubinski Orphan Nuclear Hormone Receptor RevErbalpha Modulates Expression from the Promoter of the Hydratase-dehydrogenase Gene by Inhibiting Peroxisome Proliferator-activated Receptor alpha -Dependent Transactivation J. Biol. Chem., August 6, 1999; 274(32): 22895 - 22900. [Abstract] [Full Text] [PDF]

				P. Delerive, Y. Wu, T. P. Burris, W. W. Chin, and C. S. Suen PGC-1 Functions as a Transcriptional Coactivator for the Retinoid X Receptors J. Biol. Chem., February 1, 2002; 277(6): 3913 - 3917. [Abstract] [Full Text] [PDF]