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The Gene Encoding Fibrinogen-ß Is a Target for Retinoic Acid Receptor-Related Orphan Receptor

Centre National de La Recherche Scientifique UPR9078 (C.C., B.-B.-J., J.-L.D.) Faculté de Médecine René Descartes Paris 5, site Necker, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale U545 (C.F., P.G., B.S.), Département d’Athérosclérose, Institut Pasteur de Lille, and Faculté de Pharmacie, Université de Lille II, 59019 Lille, France; and Fédération de Biochimie (M.-A.B.) , Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France

Address all correspondence and requests for reprints to: Dr. Jean-Louis Danan, Faculté de Médecine René Descartes Paris 5, site Necker, Centre National de la Recherche Scientifique Unité Propre de Recherche 9078, 156 rue de Vaugirard 75730 Paris Cedex 15, France. E-mail: danan{at}necker.fr.

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (, ß, ). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR) is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified ROR as a regulator of fibrinogen-ß gene expression in human hepatoma cells and in mouse liver. A putative ROR response element (RORE) was identified in the human fibrinogen-ß promoter. EMSA showed that ROR binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers ROR-dependent transcriptional activation to both the human fibrinogen-ß and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of ROR specifically increases endogenous fibrinogen-ß mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-ß RORE is occupied by ROR in HepG2 cells. Thus, the human fibrinogen-ß gene is a direct target for ROR. Furthermore, fibrinogen-ß mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of ROR in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.

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Nuclear Receptors:   RORα

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