Krause B R, Auerbach B J
Department of Cardiovascular Therapeutics, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Curr Opin Investig Drugs. 2001 Mar;2(3):375-81.
The apparent protective effect of high density lipoprotein cholesterol (HDL) with respect to coronary heart disease (CHD) is generally thought to reside in its ability to transport cholesterol from peripheral cells to the liver for excretion from the body. Knozon as reverse cholesterol transport (RCT), this process involves many key steps and lipoprotein interconversions, and there is no consensus as to which step is most suitable for possible drug intervention. The membrane proteins, scavenger receptor class B, type 1 (SR-B1) and the ATP-binding cassette 1 (ABC1), have been strongly implicated as being important in cholesterol efflux; the former as a bona fide receptor for HDL and the latter as a lipid transporter. Lecithin:cholesterol acyltransferase (LCAT) then esterifies the effluxed cholesterol to form cholesteryl esters (Step 2), which are then transferred to apoB-containing lipoproteins by cholesteryl ester transfer protein (CETP, Step 3). Despite the complexities and uncertainties, drugs should be developed which impact all of the above steps, and short-term endpoints need to be defined for a cautious, systematic approach to clinical evaluation.
高密度脂蛋白胆固醇（HDL）对冠心病（CHD）的明显保护作用通常被认为在于其将胆固醇从外周细胞转运至肝脏以便从体内排出的能力。这个过程被称为逆向胆固醇转运（RCT），它涉及许多关键步骤和脂蛋白的相互转化，而且对于哪个步骤最适合进行可能的药物干预尚无共识。膜蛋白，即B类清道夫受体1型（SR-B1）和ATP结合盒转运体1（ABC1），已被强烈认为在胆固醇流出中起重要作用；前者作为HDL的真正受体，后者作为脂质转运体。卵磷脂胆固醇酰基转移酶（LCAT）随后将流出的胆固醇酯化形成胆固醇酯（步骤2），然后胆固醇酯通过胆固醇酯转运蛋白（CETP）转移至含载脂蛋白B的脂蛋白（步骤3）。尽管存在复杂性和不确定性，但仍应开发影响上述所有步骤的药物，并且需要定义短期终点，以便采用谨慎、系统的方法进行临床评估。
