ABCA1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane.

Cholesterol is a major and essential component of the mammalian cell plasma membrane (PM), and the loss of cholesterol homeostasis leads to various pathologies. Cellular cholesterol uptake and synthesis are regulated by a cholesterol sensor in the endoplasmic reticulum (ER). However, it remains unclear how changes in the cholesterol level of the PM are recognized. Here, we show that the sensing of cholesterol in the PM depends on ABCA1 and the cholesterol transfer protein Aster-A, which cooperatively maintain the asymmetric transbilayer cholesterol distribution in the PM. We demonstrate that ABCA1 translocates (flops) cholesterol from the inner leaflet of the PM to the outer leaflet of the PM to maintain a low inner leaflet cholesterol level. We also found that when inner cholesterol levels were increased, Aster-A was recruited to the PM-ER contact site to transfer cholesterol to the ER. These results suggest that ABCA1 could promote an asymmetric cholesterol distribution to suppress Aster-A recruitment to the PM-ER contact site to maintain intracellular cholesterol homeostasis.

HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism.

Homozygotes for loss-of-function mutations in ABCA1 cause Tangier disease. The phenotype of their markedly reduced or loss of blood high-density lipoprotein (HDL) cholesterol, as well as examination of ATP-binding cassette transporter A1 (ABCA1)-deficient mice, proved that ABCA1 is a key player in HDL production. The ABCA1-mediated cholesterol efflux is the first step in the reverse cholesterol transport system and understanding the regulation of its expression was expected to lead to the development of anti-atherosclerotic drugs. However, from the viewpoint of intracellular cholesterol homeostasis, it is difficult to say that simple activation of ABCA1 or promotion of cholesterol efflux is a good strategy. To date, there is no evidence that HDL-increasing drugs by enhancing ABCA1 expression prevent atherosclerotic disease in humans. On the other hand, in situations where intracellular cholesterol homeostasis is disrupted by inflammation, aging, or metabolic abnormalities, a strategy that restores reduced ABCA1 expression and cholesterol efflux in a timely and localized manner may be useful.