Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice: Inhibition of 2 Independent Cellular Cholesterol–Releasing Pathways In Vivo
Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice: Inhibition of 2 Independent Cellular Cholesterol–Releasing Pathways In Vivo
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普罗布考对卵磷脂胆固醇酰基转移酶缺陷小鼠的作用：体内抑制 2 种独立的细胞胆固醇释放途径
DOI：
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
S. Yokoyama
中科院分区：
文献类型：
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作者：
S. Tomimoto;M. Tsujita;M. Okazaki;S. Usui;T. Tada;T. Fukutomi;S. Ito;M. Itoh;S. Yokoyama
翻译后摘要-细胞胆固醇释放发生至少2个不同的机制：卵磷脂-胆固醇酰基转移酶（LCAT）驱动的净流出胆固醇扩散和生成高密度脂蛋白（HDL）与细胞的胆固醇和磷脂的细胞载脂蛋白的相互作用。因此，LCAT缺乏会损害前一种途径，而后者可以被普罗布考抑制，从而干扰载脂蛋白-细胞相互作用。因此，普罗布考被给予LCAT缺陷小鼠，试图抑制这两种途径。给小鼠喂食含有0.5%普罗布考的低（0.2%）和高（1.2%）胆固醇饮食2周。LCAT缺乏和普罗布考均能显著降低血浆HDL，且二者具有协同作用。LCAT缺陷小鼠和普罗布考治疗小鼠的肾上腺和卵巢组织胆固醇含量较低，表明HDL是这些器官的主要胆固醇供应者。在低胆固醇喂养的雌性小鼠的脾脏和低胆固醇喂养的雄性小鼠的甲状腺中也中度降低。另一方面，在LCAT缺陷小鼠中，用高胆固醇饮食进行普罗布考治疗，肝脏中的酯化胆固醇含量大幅增加，但在野生型小鼠中则不然。在各组中，由于LCAT缺乏或普罗布考，其他器官（如肝、脾、胸腺、脑、红细胞、甲状腺、睾丸和主动脉）的组织胆固醇水平无显著差异。因此，载脂蛋白介导的机制在肝脏中细胞胆固醇的输出中起着重要作用，表明肝脏是HDL组装的主要场所。否则，组织胆固醇稳态可以在很大程度上保持在小鼠中，即使当新的HDL的组装被抑制普罗布考在LCAT的情况下。胆固醇的非特异性扩散可能足以维持实验条件下的稳态。
Abstract —Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol–fed female mice and in the thyroid gland of the low cholesterol–fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition.
影响因子：
15.9
作者：
FRANCIS, GA;KNOPP, RH;ORAM, JF
通讯作者：
ORAM, JF
影响因子：
15.9
作者：
Lawn, RM;Wade, DP;Oram, JF
通讯作者：
Oram, JF