Cholesterol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca2+-dependent calcineurin signaling

• Main Authors: Joel Karwatsky, Loretta Ma, Fumin Dong, Xiaohui Zha
• Format: Article
• Language: English
• Published: Elsevier 2010-05-01
• Series: Journal of Lipid Research
• Subjects: macrophage; cyclosporine A; Janus Kinase 2
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520410703

ATP-binding cassette transporter A1 (ABCA1) is required for the lipidation of apolipoprotein A-I (apoA-I), although molecular mechanisms supporting this process remain poorly defined. In this study, we focused on the role of cytosolic Ca2+ and its signaling and found that cytosolic Ca2+ was required for cholesterol efflux to apoA-I. Removing extracellular Ca2+ or chelating cytosolic Ca2+ were equally inhibitory for apoA-I lipidation. We provide evidence that apoA-I induced Ca2+ influx from the medium. We further demonstrate that calcineurin activity, the downstream target of Ca2+ influx, was essential; inhibition of calcineurin activity by cyclosporine A or FK506 completely abolished apoA-I lipidation. Furthermore, calcineurin inhibition abolished apoA-I binding and diminished JAK2 phosphorylation, an established signaling event for cholesterol efflux to apoA-I. Finally, we demonstrate that neither Ca2+ manipulation nor calcineurin inhibition influenced ABCA1's capacity to release microparticles or to remodel the plasma membrane. We conclude that this Ca2+-dependent calcineurin/JAK2 pathway is specifically responsible for apoA-I lipidation without directly modifying ABCA1 activity.