Shuvaev V V, Fujii J, Kawasaki Y, Itoh H, Hamaoka R, Barbier A, Ziegler O, Siest G, Taniguchi N
Department of Biochemistry, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biochim Biophys Acta. 1999 Aug 30;1454(3):296-308. doi: 10.1016/s0925-4439(99)00047-2.
The increased glycation of plasma apolipoproteins represents a possible major factor for lipid disturbances and accelerated atherogenesis in diabetic patients. The glycation of apolipoprotein E (apoE), a key lipid-transport protein in plasma, was studied both in vivo and in vitro. ApoE was shown to be glycated in plasma very low density lipoproteins of both normal subjects and hyperglycemic, diabetic patients. However, diabetic patients with hyperglycemia showed a 2-3-fold increased level of apoE glycation. ApoE from diabetic plasma showed decreased binding to heparin compared to normal plasma apoE. The rate of Amadori product formation in apoE in vitro was similar to that for albumin and apolipoproteins A-I and A-II. The glycation of apoE in vitro significantly decreased its ability to bind to heparin, a critical process in the sequestration and uptake of apoE-containing lipoproteins by cells. Diethylenetriaminepentaacetic acid, a transition metal chelator, had no effect on the loss of apoE heparin-binding activity, suggesting that glycation rather than glycoxidation is responsible for this effect. In contrast, glycation had no effect on the interaction of apoE with amyloid beta-peptide. ApoE glycation was demonstrated to be isoform-specific. ApoE(2) showed a higher glycation rate and the following order was observed: apoE(2)>apoE(4)>apoE(3). The major glycated site of apoE was found to be Lys-75. These findings suggest that apoE is glycated in an isoform-specific manner and that the glycation, in turn, significantly decreases apoE heparin-binding activity. We propose that apoE glycation impairs lipoprotein-cell interactions, which are mediated via heparan sulfate proteoglycans and may result in the enhancement of lipid abnormalities in hyperglycemic, diabetic patients.
血浆载脂蛋白糖基化增加是糖尿病患者脂质紊乱和动脉粥样硬化加速的一个可能的主要因素。研究了血浆中关键脂质转运蛋白载脂蛋白E（apoE）的体内和体外糖基化情况。结果显示，正常受试者和高血糖糖尿病患者的血浆极低密度脂蛋白中的apoE均发生了糖基化。然而，高血糖的糖尿病患者apoE糖基化水平增加了2至3倍。与正常血浆apoE相比，糖尿病血浆中的apoE与肝素的结合减少。体外apoE中Amadori产物的形成速率与白蛋白、载脂蛋白A-I和A-II相似。体外apoE糖基化显著降低了其与肝素结合的能力，而肝素结合是细胞隔离和摄取含apoE脂蛋白的关键过程。过渡金属螯合剂二乙烯三胺五乙酸对apoE肝素结合活性的丧失没有影响，这表明是糖基化而非糖氧化导致了这种效应。相反，糖基化对apoE与淀粉样β肽的相互作用没有影响。已证明apoE糖基化具有亚型特异性。ApoE(2)的糖基化速率较高，观察到的顺序为：apoE(2)>apoE(4)>apoE(3)。发现apoE的主要糖基化位点是Lys-75。这些发现表明，apoE以亚型特异性方式发生糖基化，而这种糖基化反过来又显著降低了apoE的肝素结合活性。我们提出，apoE糖基化损害了脂蛋白与细胞的相互作用，这种相互作用是通过硫酸乙酰肝素蛋白聚糖介导的，可能导致高血糖糖尿病患者脂质异常加剧。
