van Dam Marjel J, de Groot Eric, Clee Susanne M, Hovingh G Kees, Roelants Roosje, Brooks-Wilson Angie, Zwinderman Aeilko H, Smit Andries J, Smelt August H M, Groen Albert K, Hayden Michael R, Kastelein John J P
Departments of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Lancet. 2002 Jan 5;359(9300):37-42. doi: 10.1016/S0140-6736(02)07277-X.
Decreased concentrations of HDL cholesterol are associated with increased cardiovascular risk. These concentrations are directly related to cholesterol efflux from cells-the first step and a key process in reverse cholesterol transport. Cholesterol efflux is mediated by the ATP-binding cassette A1 transporter (ABCA1), the rate-limiting step in the production of HDL. We aimed to assess the relation between cholesterol efflux, HDL concentrations, and arterial-wall changes in individuals with impaired ABCA1 function.
We investigated 30 individuals from families with ABCA1 mutations, and 110 controls matched for age, sex, and ethnic origin. We measured concentrations of HDL cholesterol in plasma and intima-media thickness of the carotid arteries by B-mode ultrasonography in all participants. We also measured cholesterol efflux from skin fibroblasts in nine individuals with ABCA1 mutations and in ten controls.
Individuals with ABCA1 mutations had lower amounts of cholesterol efflux, lower HDL cholesterol concentrations, and greater intima-media thicknesses than controls. An intima-media thickness at the upper limit of normal (0.80 mm) was reached by age 55 years in the ABCA1 heterozygotes, and at age 80 years in unaffected controls (p<0.0001). Additionally, strong positive correlations were seen between HDL cholesterol concentrations and cholesterol efflux (r=0.90, p=0.001), and negative correlations between apolipoprotein-AI-mediated (r=-0.61, p=0.030) and HDL-particle-mediated (r=-0.60, p=0.018) efflux and intima-media thickness in the ABCA1 mutation carriers.
These results show a direct relation between ABCA1-mediated cellular cholesterol efflux and arterial-wall thickness, and therefore suggest that increasing efflux could inhibit atherosclerosis progression before the manifestation of symptomatic cardiovascular disease.
高密度脂蛋白胆固醇（HDL胆固醇）浓度降低与心血管疾病风险增加相关。这些浓度与细胞内胆固醇流出直接相关，而胆固醇流出是逆向胆固醇转运的第一步也是关键过程。胆固醇流出由ATP结合盒转运蛋白A1（ABCA1）介导，是HDL生成的限速步骤。我们旨在评估ABCA1功能受损个体的胆固醇流出、HDL浓度与动脉壁变化之间的关系。
我们研究了30名来自有ABCA1突变家族的个体，以及110名年龄、性别和种族相匹配的对照者。我们通过B型超声测量了所有参与者血浆中HDL胆固醇的浓度以及颈动脉内膜中层厚度。我们还测量了9名有ABCA1突变的个体和10名对照者皮肤成纤维细胞的胆固醇流出情况。
与对照者相比，有ABCA1突变的个体胆固醇流出量更低、HDL胆固醇浓度更低且内膜中层厚度更大。ABCA1杂合子在55岁时达到正常上限（0.80毫米）的内膜中层厚度，而未受影响的对照者在80岁时才达到（p<0.0001）。此外，在ABCA1突变携带者中，HDL胆固醇浓度与胆固醇流出之间存在强正相关（r=0.90，p=0.001），载脂蛋白A-I介导的流出（r=-0.61，p=0.030）和HDL颗粒介导的流出（r=-0.60，p=0.018）与内膜中层厚度之间存在负相关。
这些结果表明ABCA1介导的细胞胆固醇流出与动脉壁厚度之间存在直接关系，因此提示增加流出量可能在有症状的心血管疾病出现之前抑制动脉粥样硬化的进展。
