Brousseau M E, Santamarina-Fojo S, Vaisman B L, Applebaum-Bowden D, Bérard A M, Talley G D, Brewer H B, Hoeg J M
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Lipid Res. 1997 Dec;38(12):2537-47.
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme well known for its involvement in the intravascular metabolism of high density lipoproteins; however, its role in the regulation of apolipoprotein (apo) B-containing lipoproteins remains elusive. The present study was designed to investigate the metabolic mechanisms responsible for the differential lipoprotein response observed between cholesterol-fed hLCAT transgenic and control rabbits. 131I-labeled HDL apoA-I and 125I-labeled LDL kinetics were assessed in age- and sex-matched groups of rabbits with high (HE), low (LE), or no hLCAT expression after 6 weeks on a 0.3% cholesterol diet. In HE, the mean total cholesterol concentration on this diet, mg/dl (230 +/- 50), was not significantly different from that of either LE (313 +/- 46) or controls (332 +/- 52) due to the elevated level of HDL-C observed in HE (127 +/- 19), as compared with both LE (100 +/- 33) and controls (31 +/- 4). In contrast, the mean nonHDL-C concentration for HE (103 +/- 33) was much lower than that for either LE (213 +/- 39) or controls (301 +/- 55). FPLC analysis of plasma confirmed that HDL was the predominant lipoprotein class in HE on the cholesterol diet, whereas cholesteryl ester-rich, apoB-containing lipoproteins characterized the plasma of LE and, most notably, of controls. In vivo kinetic experiments demonstrated that the differences in HDL levels noted between the three groups were attributable to distinctive rates of apoA-I catabolism, with the mean fractional catabolic rate (FCR, d-1) of apoA-I slowest in HE (0.282 +/- 0.03), followed by LE (0.340 +/- 0.01) and controls (0.496 +/- 0.04). A similar, but opposite, pattern was observed for nonHDL-C levels and LDL metabolism (h-1), such that HE had the lowest nonHDL-C levels with the fastest rate of clearance (0.131 +/- 0.027), followed by LE (0.057 +/- 0.009) and controls (0.031 +/- 0.001). Strong correlations were noted between LCAT activity and both apoA-I (r= -0.868, P < 0.01) and LDL (r = 0.670, P = 0.06) FCR, indicating that LCAT activity played a major role in the mediation of lipoprotein metabolism. In summary, these data are the first to show that LCAT overexpression can regulate both LDL and HDL metabolism in cholesterol-fed rabbits and provide a potential explanation for the prevention of diet-induced atherosclerosis observed in our previous study.
卵磷脂胆固醇酰基转移酶（LCAT）是一种因参与高密度脂蛋白的血管内代谢而闻名的酶；然而，其在含载脂蛋白（apo）B的脂蛋白调节中的作用仍不清楚。本研究旨在探讨胆固醇喂养的人LCAT转基因兔和对照兔之间观察到的脂蛋白差异反应的代谢机制。在给予0.3%胆固醇饮食6周后，对年龄和性别匹配的高（HE）、低（LE）或无hLCAT表达的兔组进行了131I标记的HDL apoA-I和125I标记的LDL动力学评估。在HE组中，该饮食条件下的平均总胆固醇浓度，mg/dl（230±50），与LE组（313±46）或对照组（332±52）相比无显著差异，这是由于HE组中观察到的HDL-C水平升高（127±19），与LE组（100±33）和对照组（31±4）相比。相反，HE组的平均非HDL-C浓度（103±33）远低于LE组（213±39）或对照组（301±55）。血浆的FPLC分析证实，在胆固醇饮食下，HDL是HE组中的主要脂蛋白类别，而富含胆固醇酯、含apoB的脂蛋白则是LE组血浆的特征，最显著的是对照组血浆的特征。体内动力学实验表明，三组之间HDL水平的差异归因于apoA-I分解代谢速率的不同，apoA-I的平均分解代谢分数率（FCR，d-1）在HE组中最慢（0.282±0.03），其次是LE组（0.340±0.01）和对照组（0.496±0.04）。对于非HDL-C水平和LDL代谢（h-1）观察到类似但相反的模式，即HE组的非HDL-C水平最低，清除率最快（0.131±0.027），其次是LE组（0.057±0.009）和对照组（0.031±0.001）。LCAT活性与apoA-I（r = -0.868，P < 0.01）和LDL（r = 0.670，P = 0.06）FCR之间存在强相关性，表明LCAT活性在脂蛋白代谢的介导中起主要作用。总之，这些数据首次表明LCAT过表达可调节胆固醇喂养兔的LDL和HDL代谢，并为我们先前研究中观察到的饮食诱导动脉粥样硬化的预防提供了潜在解释。
