コレステロールホメオスタシスにおけるABCA1とABCG1の機能

抄録

Cholesterol is essential to the body as a component of cellular membranes and a source of steroid hormones, but excess cholesterol is a risk factor for atherosclerosis. ATP-binding cassette protein A1 (ABCA1) and ABCG1 play important roles in cholesterol homeostasis by removing excess cholesterol from peripheral tissues including macrophages and functioning in reverse cholesterol transport to the liver. Thus, ABCA1 and ABCG1 can be targets of drugs for atherosclerosis and hyperlipidemia. ABCA1 mediates the efflux of cholesterol and phosphatidylcholine (PC) to apolipoprotein A-I (apoA-I), which forms preβ-high density lipoprotein (HDL). ABCG1 mediates the efflux of cholesterol and sphingomyelin (SM) to preβ-HDL and HDL. Cholesterol and SM form ordered microdomains (raft domains, detergent-resistant membranes) in the plasma membrane. It was assumed that SM influences the membrane dynamics, so the cellular SM level was changed, and the effects of lipid raft on the efflux of cholesterol mediated by ABCA1 and ABCG1 were examined. It was demonstrated that the ABCA1- and ABCG1-mediated efflux of cholesterol is inverse and is correlated with the cellular SM level, respectively. The expression of ABCA1 or ABCG1 increased the amount of cholesterol available to cold methyl-β-cyclodextrin extraction even in the absence of apoA-I or HDL. These suggest that ABCA1 and ABCG1 reorganize the plasma membrane and generate more loosely packed domains, which facilitate apoA-I- or HDL-dependent cholesterol efflux, and that the membrane environment modulates the efflux of cholesterol mediated by ABCA1 and ABCG1.