Objective: The aim of this study was to determine whether ATP-binding cassette transporter A1 (ABCA1) was up-regulated by growth differentiation factor-15 (GDF-15) via the phosphoinositide 3-kinase (PI3K)/protein kinase C zeta (PKc zeta)/specificity protein 1 (SP1) pathway in THP-1 macrophages. Methods and results: We investigated the effects of different concentrations of GDF-15 on ABCA1 expression in THP-1 macrophages. The results showed that GDF-15 dramatically increased cholesterol efflux and decreased cellular cholesterol levels. In addition, GDF15 increased ABCA1 mRNA and protein levels. The effects of GDF-15 on ABCA1 protein expression and cellular cholesterol efflux were abolished by wither inhibition or depletion of PI3K, PKC zeta and SP1, respectively, suggesting the potential roles of PI3K, PKC zeta and SP1 in ABCA1 expression. Taken together, GDF-15 appears to activate PI3K, PKq and SP1 cascade, and then increase ABCA1 expression, thereby promoting cholesterol efflux and reducing foam cell formation. Conclusion: Our results suggest that GDF-15 has an overall protective effect on the progression of atherosclerosis, likely through inducing ABCA1 expression via the PI3K/PKC zeta/SP1 signaling pathway and enhancing cholesterol efflux. (C) 2014 Elsevier Inc. All rights reserved.