Assmann G, von Eckardstein A, Funke H
Institute of Clinical Chemistry and Laboratory Medicine, Westphalian Wilhelms University, Münster, Germany.
Circulation. 1993 Apr;87(4 Suppl):III28-34.
The reverse cholesterol transport model is most widely used to explain both the role of high density lipoproteins (HDL) in lipid metabolism and the inverse association between HDL cholesterol plasma concentration and the risk for coronary artery disease (CAD). As familial HDL cholesterol deficiency is frequently paralleled with a family history of premature CAD, much interest has been directed toward the molecular defects in apolipoproteins and lipid-transfer enzymes involved in the formation and metabolism of HDL. Knowledge of the basic defects in rare HDL-deficiency syndromes and apolipoprotein variants provides genetic markers of whether the presence of these molecular defects accounts for low HDL cholesterol levels and the accompanying coronary risk.
Sequence analysis of proteins or DNA from patients with HDL deficiency or hyperalphalipoproteinemia as well as from randomly screened probands has helped to identify a series of molecular defects in the genes of apolipoprotein (apo) A-I, apo A-II, apo A-IV, apo C-III, lecithin cholesterol acyltransferase, and cholesterol ester-transfer protein. Some of these mutations were associated with absent and low levels of HDL cholesterol in homozygous and heterozygous carries, respectively, but only a few homozygotes were at an increased risk of CAD. These mutations were invaluable for gaining insight into structural-functional relations in HDL metabolism.
Mutations in the genes of apo A-I, apo A-II, apo A-IV, apo C-III, lecithin cholesterol acyltransferase, and cholesterol ester-transfer protein can influence HDL cholesterol plasma concentrations but do not account for the coronary risk associated with low HDL cholesterol levels. In general, these observations suggest that the low HDL concentrations in CAD patients are not a reflection of impaired reverse cholesterol transport but rather of some other metabolic disturbances, such as catabolism of triglyceride-rich particles.
逆向胆固醇转运模型被广泛用于解释高密度脂蛋白（HDL）在脂质代谢中的作用以及HDL胆固醇血浆浓度与冠状动脉疾病（CAD）风险之间的负相关关系。由于家族性HDL胆固醇缺乏常与早发CAD家族史并存，人们对参与HDL形成和代谢的载脂蛋白及脂质转运酶的分子缺陷产生了浓厚兴趣。了解罕见HDL缺乏综合征和载脂蛋白变体的基本缺陷，可为这些分子缺陷是否导致HDL胆固醇水平降低及伴随的冠心病风险提供遗传标记。
对HDL缺乏或高α脂蛋白血症患者以及随机筛选的先证者的蛋白质或DNA进行序列分析，有助于识别载脂蛋白（apo）A-I、apo A-II、apo A-IV、apo C-III、卵磷脂胆固醇酰基转移酶和胆固醇酯转移蛋白基因中的一系列分子缺陷。其中一些突变分别与纯合子和杂合子携带者中HDL胆固醇的缺失和低水平相关，但只有少数纯合子患CAD的风险增加。这些突变对于深入了解HDL代谢中的结构-功能关系非常宝贵。
apo A-I、apo A-II、apo A-IV、apo C-III、卵磷脂胆固醇酰基转移酶和胆固醇酯转移蛋白基因中的突变可影响HDL胆固醇血浆浓度，但不能解释与低HDL胆固醇水平相关的冠心病风险。总体而言，这些观察结果表明，CAD患者中HDL浓度低并非逆向胆固醇转运受损的反映，而是其他一些代谢紊乱的表现，如富含甘油三酯颗粒的分解代谢。
