FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol

•ABCA6 is identified as a novel target gene of FoxO in human endothelial cells.•ABCA6 is regulated by endogenous IGF-PI3K-Akt-FoxO signaling pathways.•The cellular distribution of ABCA6 fusion protein is determined.•ABCA6 is responsive to cholesterol in endothelial cells. ATP-binding-cassette (ABC) proteins have been recognized as key players in cellular physiological transport processes. ABC transporter A6 (ABCA6) is a member of the ABC subfamily A. Although it was cloned more than 10 years ago, its expression regulation, subcellular localization, and physiologic function remain largely unknown. We here demonstrated that expression of ABCA6 was Forkhead box O (FoxO)-dependent in human endothelial cell line EA.hy926 and human umbilical vein endothelial cells. Two functional FoxO-responsive elements were identified in ABCA6 promoter and characterized in detail. ABCA6 mRNA was suppressed by insulin-like growth factor-1 which stimulates the phosphorylation and inactivation of FoxOs while inhibitor of phosphatidylinositol 3-kinase had the opposite effect. By immunofluorescence and confocal microscopy, ABCA6 protein is localized primarily in an intracellular compartment, likely representing the Golgi apparatus. ABCA6 mRNA was demonstrated to be responsive to cholesterol loading as well as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors in human endothelial cells. Our data provide evidence for an essential role of FoxO proteins in the transcription of ABCA6 in human vascular endothelial cells. Based on its cholesterol responsiveness, a potential involvement of ABCA6 in intracellular lipid transport processes may be anticipated.