Journal
JOURNAL OF LIPID RESEARCH
Volume 51, Issue 5, Pages 1144-1156Publisher
ELSEVIER
DOI: 10.1194/jlr.M003145
Keywords
macrophage; cyclosporine A; Janus Kinase 2
Categories
Funding
- Heart and Stroke Foundation of Ontario [T6384]
- Heart and Stroke Foundation of Canada-AstraZeneca
- Ontario Scholarship in Science and Technology
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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.-Karwatsky, J., L. Ma, F. Dong, and X. Zha. Cholesterol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca2+-dependent calcineurin signaling. J. Lipid Res. 2010. 51: 1144-1156.
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