Commentary on "the ATPase activity of ABCA1 is increased by cholesterol in the presence of anionic lipids".

High-density lipoprotein (HDL) mediates reverse cholesterol transport from the peripheral tissues to the liver and plays a crucial role in preventing atherosclerosis. ATP-binding cassette transporter A1 (ABCA1) is essential for HDL biogenesis; however, whether cholesterol serves as a substrate that is directly transported by this protein remains unclear. Sakata et al. reconstituted ABCA1 into phospholipid liposomes devoid of cholesterol during assembly, enabling an accurate evaluation of substrate specificity. Their findings demonstrated that cholesterol, but not plant sterols, stimulate ABCA1 ATPase activity, indicating that cholesterol is the preferred substrate. Moreover, ABCA1 activity was found to require anionic phospholipids, suggesting that the membrane lipid composition regulates its function. These results provide biochemical evidence of ATP-driven cholesterol transport by ABCA1 and establish a versatile platform for future studies on lipid homeostasis and HDL formation.