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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1186.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor ROR

Annelise Genoux; Hélène Dehondt; Audrey Helleboid-Chapman; Christian Duhem; Dean W. Hum; Geneviève Martin; Len A. Pennacchio; Bart Staels; Jamila Fruchart-Najib; Jean-Charles Fruchart

From Département d’Athérosclérose (A.G., H.D., A.H-C., C.D., B.S., J.F-N, J-C.F.), U.545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie de Lille, Lille Cedex, France; Genfit SA (D.W.H., G.M.), Loos, France; Genomics Division (L.A.P.), Lawrence Berkeley National Laboratory, Berkeley, Calif.

Correspondence to Jamila Fruchart-Najib, U.545 INSERM, Université de Lille II, 885 avenue Eugéne Avinée, 59120 Loos, France. E-mail jfruchart{at}pharma.univ-lille2.fr

Objective— The newly identified apolipoprotein A5 (APOA5), selectively expressed in the liver, is a crucial determinant of plasma triglyceride levels. Because elevated plasma triglyceride concentrations constitute an independent risk factor for cardiovascular diseases, it is important to understand how the expression of this gene is regulated. In the present study, we identified the retinoic acid receptor-related orphan receptor- (ROR) as a regulator of human APOA5 gene expression.

Methods and Results— Using electromobility shift assays, we first demonstrated that ROR1 and ROR4 proteins can bind specifically to a direct repeat 1 site present at the position –272/–260 in the APOA5 gene promoter. In addition, using transient cotransfection experiments in HepG2 and HuH7 cells, we demonstrated that both ROR1 and ROR4 strongly increase APOA5 promoter transcriptional activity in a dose-dependent manner. Finally, adenoviral overexpression of hROR in HepG2 cells led to enhanced hAPOA5 mRNA accumulation. We show that the homologous region in mouse apoa5 promoter is not functional. Moreover, we show that in staggerer mice, apoa5 gene is not affected by ROR.

Conclusions— These findings identify ROR1 and ROR4 as transcriptional activators of human APOA5 gene expression. These data suggest an additional important physiological role for ROR in the regulation of genes involved in lipid homeostasis and probably in the development of atherosclerosis.

Apolipoprotein A5 has recently been identified as a crucial determinant of plasma triglyceride levels. Our results showed that ROR upregulates human APOA5 but has no effect on mouse apoa5 gene. These data suggest an additional important physiological role for ROR in the regulation of genes involved in lipid homeostasis in human and probably in the development of atherosclerosis.

Key Words: apolipoprotein A5 • nuclear receptor ROR • triglyceride homeostasis • transcriptional regulation

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