Brewer H Bryan, Santamarina-Fojo Silvia
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20894, USA.
Am J Cardiol. 2003 Aug 21;92(4B):10K-16K. doi: 10.1016/s0002-9149(03)00769-0.
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.
高密度脂蛋白（HDL）胆固醇水平低是冠状动脉疾病的一个危险因素，并且有证据表明提高HDL胆固醇水平可降低心血管风险。伴有或不伴有甘油三酯升高的低HDL胆固醇表型在因心血管疾病住院的患者中至少与高胆固醇血症一样常见，它是糖尿病和代谢综合征的特征，而这些疾病与心血管风险增加相关。最近的研究阐明了HDL降低心血管风险的机制，支持了在调脂治疗中以HDL为靶点的理论依据。具体而言，HDL（1）在称为逆向胆固醇转运的过程中将外周细胞中多余的胆固醇转运至肝脏进行清除，（2）减少低密度脂蛋白（LDL）的氧化修饰，以及（3）抑制细胞因子诱导的内皮细胞上细胞黏附分子的表达。对新描述的三磷酸腺苷结合盒蛋白A1（ABCA1）转运体的研究已证实该转运体在调节血浆HDL水平以及肝脏和外周细胞内胆固醇水平方面起着关键作用。细胞内胆固醇水平升高会刺激肝脏X受体途径，增强ABCA1的表达，这会增加细胞内多余胆固醇向细胞表面的转运，以便与脂质含量低的载脂蛋白A-I相互作用形成新生HDL。新生HDL有助于清除额外的多余细胞胆固醇，这些胆固醇被卵磷脂胆固醇酰基转移酶酯化，使新生HDL转化为成熟的球形HDL。在常规饮食或西方饮食的小鼠中过表达ABCA1会导致血浆HDL显著增加、LDL增加以及胆固醇向肝脏的转运增加。在高胆固醇/胆酸盐饮食条件下，过表达ABCA1的转基因小鼠HDL增加、LDL减少、HDL介导的胆固醇向肝脏的通量增加且动脉粥样硬化减轻。正在进行的关于HDL降低动脉粥样硬化风险机制的研究将为开发降低动脉粥样硬化风险的药物提供几个新靶点。
