Bilheimer D W, Stone N J, Grundy S M
J Clin Invest. 1979 Aug;64(2):524-33. doi: 10.1172/JCI109490.
To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of (125)I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the (125)I-LDL turnover in all seven of the homozygotes. With regard to (125)I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. THE DATA INDICATE THAT THE SINGLE GENE DEFECT IN FH PRODUCES TWO DISTINCT ABNORMALITIES OF LDL METABOLISM: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at congruent with 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.
为研究家族性高胆固醇血症（FH）中的基因剂量效应，我们对一组特征明确的杂合子（n = 7）或纯合子（n = 7）FH患者进行了代谢研究，并将结果与正常受试者（n = 6）的结果进行比较。在所有正常受试者、除一名以外的所有FH杂合子以及所有纯合子中测量了（125）I标记的低密度脂蛋白（LDL）的周转率。在所有七名纯合子中，同时进行了化学胆固醇平衡与（125）I-LDL周转率的测定。关于（125）I-LDL周转率，拥有两剂突变FH基因的FH纯合子，其载脂蛋白LDL（apoLDL）合成速率增加了两倍，而载脂蛋白的分数分解代谢率（FCR）仅为正常的三分之一左右。只有一剂突变FH基因的杂合子，这两个参数均表现为中间值；即，FCR为正常的三分之二，apoLDL合成速率比正常高1.7倍。数据表明，FH中的单基因缺陷导致LDL代谢出现两种不同的异常：（a）apoLDL合成速率增加，（b）apoLDL分解代谢效率降低。这两种缺陷在FH纯合子中比在杂合子中更严重。纯合子中apoLDL的FCR似乎固定在约17%/天，而血浆LDL水平变化约两倍。这些发现表明，在这七名患者中观察到的血浆LDL水平的两倍变化是由血浆apoLDL合成速率的变化引起的。与这一结论一致的是，在七名FH纯合子中，血浆LDL水平与apoLDL合成速率之间的相关性为0.943。通过化学胆固醇平衡测定的全身胆固醇合成速率在正常人与携带一个或两个突变FH基因的患者之间似乎没有明显差异。两名最年轻的FH纯合子表现出胆固醇过量产生，但其他五名没有。在这些患者中未观察到胆汁酸代谢的一致异常。由于LDL上胆固醇的每日血浆通量比每天产生的胆固醇量大约大三倍，从LDL降解中释放的大量胆固醇必须被重新利用。
