ABCA1 expression disrupts lipid raft plasma membrane microdomains through its ATPase-related functions

Abstract

The ATP-binding cassette transporter A1 (ABCA1) is known to mediate cholesterol efflux to lipid-poor apolipoprotein A-I. In addition, ABCA1 has been shown to influence functions of the plasma membrane, such as endocytosis and phagocytosis. Here, we report that ABCA1 expression results in a significant redistribution of plasma membrane cholesterol and sphingomyelin from lipid rafts to non-raft regions. Caveolin, a lipid raft/caveolae protein marker, also redistributes from punctate, caveolae-like structures to the general area of the plasma membrane upon expression of ABCA1. Furthermore, we observed a significant reduction of Akt activation in ABCA1-expressing cells, consistent with lipid raft disruption. Cholesterol content in the plasma membrane was, however, not altered. Moreover, we provide evidence that the non-functional A937V-ABCA1 mutant, with a point mutation in the nucleotide binding domain, fails to redistribute cholesterol, sphingomyelin, or caveolin. A937V also fails to influence Akt activation. Finally, we show that apolipoprotein A-1 preferentially associates with non-raft membranes in ABCA1-expressing cells. Our results thus demonstrate that ABCA1 causes a change in overall lipid packing of the plasma membrane, likely through its ATPase-related functions. Such reorganization by ABCA1 effectively expands the non-raft membrane fractions and, consequently, pre-conditions cells for cholesterol efflux.