By contrast, ABCA1 may function in the “housekeeping” removal of cholesterol from non-raft domains, because detectable amounts of ABCA1 proteins are expressed in macrophages, fibroblasts, and astrocytes, even when intracellular cholesterol levels are not high. Furthermore, ABCG1 mediates the efflux of 7-ketocholesterol, which is incorporated into raft domains and induces cell death. When 7ketocholesterol is associated with raft domains, ABCG1 may remove 7-ketocholesterol rapidly from raft domains in order to protect cells from the toxicity of 7-ketocholesterol. The physiological significance of the distinct distribution of ABCA1, ABCG1, and ABCG4 in the plasma Remdesivir GS-5734 membrane may be related to the different roles among these ABC proteins on the sterol efflux in vivo. Although ABCA1, ABCG1, and ABCG4 are localized to distinct membrane meso-domains, they all seem to disturb raft domain structures, as shown in Fig. 6, 7, and 8. It has been shown that ABCA1 and ABCG1 increase the amounts of cholesterol accessible to cholesterol oxidase, and that ABCA1 increases the amount of cholesterol available to cold MbCD extraction. Similarly, we showed that ABCA1, ABCG1, and ABCG4 increased the amount of cholesterol extracted by cold MbCD in Fig. 6, suggesting that ABCA1, ABCG1, and ABCG4 increase the area of non-raft domains. ABCG1 and ABCG4 decreased the distribution of caveolin-1 to raft domains in our study, and ABCA1 has also been reported to alter the distribution of caveolin-1, suggesting that ABCA1, ABCG1, and ABCG4 disturb raft domains. Furthermore, ABCG1 and ABCG4 decreased cholera toxin binding to GM1 as shown in Fig. 8. This is coincident with a study showing cholera toxin binding was increased in macrophages from Abcg1 knockout mice. Together, these findings suggest that ABCA1, ABCG1, and ABCG4 disrupt raft domains. The mechanism of the disruption of the raft domains remains elusive, but we propose that ABCA1, ABCG1, and ABCG4 transport lipids in the plasma membrane, thereby reducing the interactions of these lipids with other lipids, with proteins including caveolin-1, and/or with gangliosides including GM1, leading to the reorganization of lipids and the disruption of raft domains. The fact that the three cholesterol transporters mediate similar effects on raft domains suggests that cholesterol efflux by ABCA1, ABCG1, and ABCG4 is based on similar mechanisms. The molecular mechanisms underlying cholesterol efflux to apoA-I or HDL may be that ABCA1, ABCG1, and ABCG4 provide easily removable cholesterol, which is extracted by apoA-I or HDL, by reorganizing membrane mesodomains. However, we cannot exclude the possibility that other mechanisms also affect cholesterol efflux.