Colestipol-induced changes in LDL composition and metabolism. II. Studies in humans.
Colestipol-induced changes in LDL composition and metabolism. II. Studies in humans.
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发表时间：
1989-02
影响因子：
6.5
通讯作者：
S. Young;J. Witztum;T. Carew;R. Krauss;F. Lindgren
中科院分区：
文献类型：
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作者：
S. Young;J. Witztum;T. Carew;R. Krauss;F. Lindgren
我们研究了胆汁酸螯合剂盐酸考来替泊对人低密度脂蛋白（LDL）组成和代谢的影响。与LDL载脂蛋白B（apoB）相比，考来替泊治疗使LDL胆固醇不成比例地降低，导致LDL胆固醇/apoB比值显著下降。电子显微镜显示LDL颗粒变小，分析超速离心表明考来替泊治疗选择性地去除了浮力更大、Sf值为6 - 7的较大LDL颗粒。因此，考来替泊治疗产生的LDL颗粒更小、更致密，且胆固醇与蛋白质的比值降低。为了确定改变后的LDL是否具有不同的代谢特性，在考来替泊治疗前和治疗期间从受试者中分离出自体LDL，然后在同一患者治疗期间同时测定其部分分解代谢率（FCR）。在6名受试者中进行了8次LDL周转研究，比较了治疗期间分离的LDL（Rx - LDL）和未治疗时分离的LDL（Con - LDL）的分解代谢情况。所有受试者对考来替泊治疗都有反应，LDL胆固醇平均下降29%。在6名受试者中的4名以及8次研究中的6次，Rx - LDL的FCR明显慢于Con - LDL的FCR。这些研究表明，药物干预可能会改变LDL颗粒的亚群，从而改变LDL的整体组成。这种改变可能会独立影响LDL的内在代谢行为。我们建议，在旨在评估所研究的干扰因素的总体影响的动力学研究中，需要考虑药物（或饮食）诱导的LDL组成变化。
We investigated the effect of the bile acid sequestrant, colestipol hydrochloride, on the composition and metabolism of human low density lipoprotein (LDL). Colestipol treatment produced a disproportionate decrease in LDL cholesterol compared to LDL apoB, resulting in a significant decrease in the LDL cholesterol/apoB ratio. Electron microscopy revealed that LDL particles were smaller in size and analytical ultracentrifugation demonstrated that colestipol therapy selectively depleted larger, more buoyant LDL particles of Sf degrees 6-7. Thus, colestipol therapy produced LDL that were smaller in size, more dense, and characterized by a decreased cholesterol to protein ratio. To determine whether the altered LDL had different metabolic properties, autologous LDL was isolated from subjects before and during colestipol therapy and their fractional catabolic rates (FCR) were then simultaneously determined in the same patient while on therapy. Eight LDL turnover studies comparing the catabolism of LDL isolated during therapy (Rx-LDL) and LDL isolated off therapy (Con-LDL) were performed in six subjects. All subjects responded to colestipol treatment, with an average 29% fall in LDL cholesterol. In four of six subjects, and in six of eight studies, the FCR of Rx-LDL was substantially slower than that of Con-LDL. These studies demonstrate that a drug intervention may alter subpopulations of LDL particles in such a way that overall LDL composition is changed. This alteration may independently affect the intrinsic metabolic behavior of the LDL. We suggest that such drug- (or dietary-) induced changes in LDL composition need to be considered in kinetic studies designed to assess the overall impact of the perturbation being studied.