Low levels of
high-density lipoprotein (
HDL) cholesterol constitute a risk factor for
coronary artery disease, and there is evidence that increasing
HDL cholesterol levels reduces cardiovascular risk. The phenotype of low
HDL cholesterol with or without elevated
triglycerides is at least as common in patients hospitalized for
cardiovascular disease as is
hypercholesterolemia, and it is characteristic of diabetes and the
metabolic syndrome, conditions associated with increased cardiovascular risk. Recent studies have elucidated mechanisms by which HDL acts to reduce cardiovascular risk, bolstering the rationale for targeting of HDL in
lipid-modifying
therapy. In particular,
HDL (1) carries excess
cholesterol from peripheral cells to the liver for removal in the process termed reverse
cholesterol transport, (2) reduces oxidative modification of
low-density lipoproteins (
LDL), and (3) inhibits
cytokine-induced expression of cellular adhesion molecules on endothelial cells. Studies of the newly described
adenosine triphosphate-binding cassette
protein A1 (ABCA1) transporter have established a crucial role for this transporter in modulating the levels of plasma HDL and intracellular
cholesterol in the liver as well as in peripheral cells. Elevated levels of intracellular
cholesterol stimulate the
liver X receptor pathway, enhancing the expression of ABCA1, which increases intracellular trafficking of excess
cholesterol to the cell surface for interaction with
lipid-poor
apolipoprotein A-I to form
nascent HDL.
Nascent HDL facilitates the removal of additional excess cellular
cholesterol, which is esterified by
lecithin-cholesterol acyltransferase with conversion of the
nascent HDL to mature spherical HDL. Overexpression of ABCA1 in mice on a regular chow or Western diet results in a marked increase in plasma HDL, increased
LDL, and increased transport of
cholesterol to the liver. On a high
cholesterol/
cholate diet, transgenic mice overexpressing ABCA1 have increased HDL, reduced
LDL, increased HDL-mediated
cholesterol flux to the liver, and reduced
atherosclerosis. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of
atherosclerosis will provide several new targets for the development of drugs to decrease the risk of
atherosclerosis.