Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORα

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-alpha (ROR alpha) as a regulator of human APOA5 gene expression. Methods and Results - Using electromobility shift assays, we first demonstrated that ROR alpha 1 and ROR alpha 4 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 ROR alpha 1 and ROR alpha 4 strongly increase APOA5 promoter transcriptional activity in a dose-dependent manner. Finally, adenoviral overexpression of hROR alpha 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 alpha. Conclusions - These findings identify ROR alpha 1 and ROR alpha 4 as transcriptional activators of human APOA5 gene expression. These data suggest an additional important physiological role for ROR alpha in the regulation of genes involved in lipid homeostasis and probably in the development of atherosclerosis.