MODIFICATION OF LOW-DENSITY-LIPOPROTEIN BY ADVANCED GLYCATION END-PRODUCTS CONTRIBUTES TO THE DYSLIPIDEMIA OF DIABETES AND RENAL-INSUFFICIENCY
MODIFICATION OF LOW-DENSITY-LIPOPROTEIN BY ADVANCED GLYCATION END-PRODUCTS CONTRIBUTES TO THE DYSLIPIDEMIA OF DIABETES AND RENAL-INSUFFICIENCY
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DOI：
10.1073/pnas.91.20.9441
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发表时间：
1994-09-27
影响因子：
11.1
通讯作者：
VLASSARA, H
中科院分区：
文献类型：
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作者：
BUCALA, R;MAKITA, Z;VLASSARA, H
动脉粥样硬化在糖尿病或肾功能不全患者中发展迅速。在这些情况下，血浆脂蛋白谱经常异常，反映出含有载脂蛋白B(ApoB)的成分极低密度脂蛋白(VLDL)和低密度脂蛋白(LDL)水平升高，循环中晚期糖基化终产物(AGEs)水平也高，糖尿病和终末期肾病(ESRD)也会发生。这些产品来自葡萄糖衍生的Amadori产品，并包括AGE修饰的多肽(AGE-多肽)，它是AGE修饰的组织蛋白分解代谢的结果。由于肾功能不全，AGE-多肽已被证明能使蛋白质氨基交联，并在血浆中蓄积。为了探讨糖尿病和终末期肾病血脂异常的可能机制，我们研究了循环AGEs直接与血浆脂蛋白反应以阻止它们被组织低密度脂蛋白受体识别的可能性。年龄特异性ELISA法显示糖尿病或终末期肾病患者血浆中AGE修饰的低密度脂蛋白水平显著高于正常对照组。当天然低密度脂蛋白与人工合成的AGE多肽或直接从患者血浆中分离的AGE多肽孵育时，AGE-LDL在体外很容易形成。体外经AGE多肽修饰的低密度脂蛋白与糖尿病肾功能不全患者血浆中的修饰水平相同，当注射到表达人低密度脂蛋白受体的转基因小鼠中时，低密度脂蛋白的清除动力学明显受损。这些数据表明，AGE修饰显著削弱了低密度脂蛋白受体介导的清除机制，并可能导致糖尿病或肾功能不全患者的低密度脂蛋白水平升高。进一步支持这一假设的是，观察到糖尿病患者服用晚期糖基化抑制剂氨基胍后，循环中的低密度脂蛋白水平降低了28%。
Atherosclerosis develops rapidly in patients with diabetes or renal insufficiency. Plasma lipoprotein profiles are frequently abnormal in these conditions and reflect an elevation in the level of the apoprotein B (ApoB)-containing components very low density lipoprotein (VLDL) and low density lipoprotein (LDL), High levels of circulating advanced glycation end products (AGEs) also occur in diabetes and end-stage renal disease (ESRD). These products arise from glucose-derived Amadori products and include AGE-modified peptides (AGE-peptides) which result from the catabolism of AGE-modified tissue proteins. AGE-peptides have been shown to crosslink protein amino groups and to accumulate in plasma as a consequence of renal insufficiency. To address potential mechanisms for the dyslipidemia of diabetes and ESRD, we investigated the possibility that circulating AGEs react directly with plasma lipoproteins to prevent their recognition by tissue LDL receptors. AGE-specific ELISA showed a significantly increased level of AGE-modified LDL in the plasma of diabetic or ESRD patients compared with normal controls. AGE-LDL formed readily in vitro when native LDL was incubated with either synthetic AGE-peptides or AGE-peptides isolated directly from patient plasma. LDL which had been modified by AGE-peptides in vitro to the same level of modification as that present in the plasma of diabetics with renal insufficiency exhibited markedly impaired clearance kinetics when injected into transgenic mice expressing the human LDL receptor. These data indicate that AGE modification significantly impairs LDL-receptor-mediated clearance mechanisms and may contribute to elevated LDL levels in patients with diabetes or renal insufficiency. This hypothesis was further supported by the observation that the administration of the advanced glycation inhibitor aminoguanidine to diabetic patients decreased circulating LDL levels by 28%.