Guo H C, Chapman M J, Bruckert E, Farriaux J P, De Gennes J L
Lipoprotein and Atherogenesis Research Unit, INSERM U.321, Hôpital de la Pitié, Paris.
Atherosclerosis. 1991 Jan;86(1):69-83. doi: 10.1016/0021-9150(91)90100-h.
Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.
纯合子家族性高胆固醇血症（FH）是一种遗传性疾病，其特征为细胞低密度脂蛋白（LDL）受体功能缺陷、循环中LDL浓度显著升高以及动脉粥样硬化提前发生。在这种疾病中，除LDL外，含载脂蛋白B（apo B）的脂蛋白的潜在致动脉粥样硬化作用尚不确定。我们描述了一组8名无亲缘关系的纯合子FH患者中脂蛋白（a）[Lp（a）]的定量和定性特征与apo（a）表型的关系。与健康受试者相比，血浆Lp（a）水平显著升高（2.5倍；平均50±32mg/dl）。apo（a）的S2同工型出现频率最高（8名患者中有6名）；3名患者出现罕见的B同工型。纯合子FH患者的血浆Lp（a）水平与apo（a）表型预测的水平不相符。对Lp（a）的密度分布以及Lp（a）颗粒大小和密度异质性的分析未发现纯合子FH的任何特征性异常。然而，对Lp（a）颗粒水合密度与apo（a）同工型含量关系的比较显示，同工型对该参数有明显影响；因此，在一名B/S2杂合子患者中，仅含同工型B、含B和S2以及仅含S2的Lp（a）组分的密度分布表明，apo（a）的表观分子量在控制所得Lp（a）颗粒的水合密度和大小方面起决定性作用。事实上，表达高分子量S2同工型的患者Lp（a）均呈现致密形式（水合密度约为1.055g/ml）。在呈现两种apo（a）同工型的受试者中，每种同工型存在于不同的脂蛋白颗粒上；在这种情况下，密度较高的同工型血浆水平占主导，这表明在形成速率、组织分解代谢速率、颗粒在血浆中的稳定性方面存在差异，或这些机制的组合。综合考虑，我们的数据可以解释为，纯合子FH患者循环中Lp（a）水平升高可能反映生物合成增加、通过细胞LDL受体途径的分解代谢减少或两者兼而有之。
