Retinoic acid receptor-related orphan receptor-alpha (ROR alpha) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR alpha regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR alpha also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR alpha increased the endogenous expression of ApoAV in HepG2 cells and ROR alpha also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate ROR alpha transactivation, one of which overlaps with a previously identified binding site for PPAR alpha. Together, these results suggest a novel mechanism whereby ROR alpha modulates lipid metabolism and implies ROR alpha as a potential target for the treatment of dyslipidemia and atherosclerosis. (c) 2005 Elsevier Inc. All rights reserved.