Brousseau M E, Santamarina-Fojo S, Zech L A, Bérard A M, Vaisman B L, Meyn S M, Powell D, Brewer H B, Hoeg J M
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Invest. 1996 Apr 15;97(8):1844-51. doi: 10.1172/JCI118614.
Lecithin cholesterol acyltransferase (LCAT) is an enzyme involved in the intravascular metabolism of high density lipoproteins (HDLs). Overexpression of human LCAT (hLCAT) in transgenic rabbits leads to gene dose-dependent increases of total and HDL cholesterol concentrations. To elucidate the mechanisms responsible for this effect, 131I-HDL apoA-I kinetics were assessed in age- and sex-matched groups of rabbits (n=3 each) with high, low, or no hLCAT expression. Mean total and HDL cholesterol concentrations (mg/dl), respectively, were 162+/-18 and 121+/-12 for high expressors (HE), 55+/-6 and 55+/-10 for low expressors (LE), and 29+/-2 and 28+/-4 for controls. Fast protein liquid chromatography analysis of plasma revealed that the HDL of both HE and LE were cholesteryl ester and phospholipid enriched, as compared with controls, with the greatest differences noted between HE and controls. These compositional changes resulted in an incremental shift in apparent HDL particle size which correlated directly with the level of hLCAT expression, such that HE had the largest HDL particles and controls the smallest. In vivo kinetic experiments demonstrated that the fractional catabolic rate(FCR, d(-1)) of apoA-I was slowest in HE (0.328+/-0.03) followed by LE (0.408+/-0.01) and, lastly, by controls (0.528+/-0.04). ApoA-I FCR was inversely associated with HDL cholesterol level (r=-0.851,P<0.01) and hLCAT activity (r=-0.816, P<0.01). These data indicate that fractional catabolic rate is the predominant mechanism by which hLCAT overexpression differentially modulates HDL concentrations in this animal model. We hypothesize that LCAT-induced changes in HDL composition and size ultimately reduce apoA-I catabolism by altering apoA-I conformation and/or HDL particle regeneration.
卵磷脂胆固醇酰基转移酶（LCAT）是一种参与高密度脂蛋白（HDL）血管内代谢的酶。在转基因兔中过表达人LCAT（hLCAT）会导致总胆固醇和HDL胆固醇浓度呈基因剂量依赖性增加。为了阐明造成这种效应的机制，在年龄和性别匹配的兔组（每组n = 3）中评估了131I-HDL载脂蛋白A-I（apoA-I）的动力学，这些兔组分别具有高、低或无hLCAT表达。高表达组（HE）的平均总胆固醇和HDL胆固醇浓度（mg/dl）分别为162±18和121±12，低表达组（LE）为55±6和55±10，对照组为29±2和28±4。血浆的快速蛋白质液相色谱分析显示，与对照组相比，HE和LE的HDL都富含胆固醇酯和磷脂，HE与对照组之间的差异最大。这些组成变化导致表观HDL颗粒大小逐渐改变，这与hLCAT表达水平直接相关，使得HE具有最大的HDL颗粒，而对照组的最小。体内动力学实验表明，apoA-I的分数分解代谢率（FCR，d(-1)）在HE中最慢（0.328±0.03），其次是LE（0.408±0.01），最后是对照组（0.528±0.04）。ApoA-I FCR与HDL胆固醇水平呈负相关（r = -0.851，P<0.01），与hLCAT活性呈负相关（r = -0.816，P<0.01）。这些数据表明，分数分解代谢率是hLCAT过表达在该动物模型中差异调节HDL浓度的主要机制。我们推测，LCAT诱导的HDL组成和大小变化最终通过改变apoA-I构象和/或HDL颗粒再生来减少apoA-I分解代谢。
