Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small a, preb-1, and other preb forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Preb-1-like HDL had a plasma residence time of 8 6 6 h and was converted entirely to large a-HDL having residence times of 13-14 h. Small a-HDL was converted entirely to large a-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis. In 1951, it was reported that a minor component of the plasma lipoproteins was paradoxically reduced in patients who had coronary heart disease (CHD), in contrast to the bulk of plasma lipoproteins that were notably increased (1). Nine years later, the first prospective studies confirmed that a low plasma HDL cholesterol concentration is a predictor of CHD (2), as have subsequent studies of large populations (3, 4). A low plasma HDL cholesterol concentration is also a predictor of stroke (5). The relation between HDL cholesterol and CHD is strong and consistent among men and women, young and old, and in those with low or high LDL cholesterol concentrations (6); and the influence on HDL cholesterol on risk of CHD persists even during treatment with statins at typical (7) or high doses (8). These findings support the theory that HDL is a component of the lipoprotein system that not only protects against the atherogenic actions of VLDL and LDL, but also may be essential to prevent atherosclerosis even when plasma LDL cholesterol concentration is very low.HDL transports cholesterol from peripheral tissues, including arterial wall, to the liver directly or by transferring cholesterol to VLDL and LDL in plasma, which eventually deliver much of their cholesterol to the liver (9, 10). The liver can then channel the excess cholesterol for excretion into the bile. This complex process is called reverse cholesterol transport. The step that initiates cholesterol removal from macrophages, the predominant cholesterol-loaded cell type in atherosclerosis, is activation by HDL of cholesterol transporters. Although several cholesterol transporters exist in macro...

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