Balasubramaniam S, Szanto A, Roach P D
Lipid Department, University of New South Wales School of Medicine, St. Vincent's Hospital, Darlinghurst, Australia.
Biochem J. 1994 Feb 15;298 ( Pt 1)(Pt 1):39-43. doi: 10.1042/bj2980039.
On the basis of studies in vivo and in vitro that involved the use of pharmacological amounts of drugs and hormones or excess cholesterol supplementation, the expression of the low-density lipoprotein (LDL) receptor appears to be tightly coupled to the regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity and to extracellular levels of LDL. The present study was undertaken to see how these three entities are regulated under normal physiological conditions over a 24 h period. The results show that, in the rat, hepatic LDL-receptor expression and plasma LDL levels exhibit diurnal periodicity, with a 2-3-fold difference between the peak and trough of each rhythm. Both rhythms showed high inverse correlation (r = -0.86, P < 0.01), plasma LDL levels being lowest at the onset of darkness when LDL-receptor expression was at its peak. The results also showed that the LDL-receptor protein in rat liver has a shorter half-life than that reported for cultured fibroblasts or HepG2 cells. The maximal expression of the LDL receptor occurred several hours before the peak activity of HMG-CoA reductase and appeared not to be influenced by cellular or membrane cholesterol levels during the 24 h cycle. Treatment with dexamethasone increased the LDL-receptor activity significantly at both the lowest and highest points of the rhythm, but the receptor rhythm was still maintained, suggesting that the signal for the circadian variation of the receptor expression is not mediated by adrenal hormones.
基于体内和体外研究，这些研究涉及使用药理剂量的药物、激素或过量补充胆固醇，低密度脂蛋白（LDL）受体的表达似乎与3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶活性的调节以及细胞外LDL水平紧密相关。本研究旨在观察这三个实体在正常生理条件下24小时内是如何被调节的。结果表明，在大鼠中，肝脏LDL受体表达和血浆LDL水平呈现昼夜周期性，每个节律的峰值和谷值之间存在2至3倍的差异。两种节律均显示出高度负相关（r = -0.86，P < 0.01），在黑暗开始时血浆LDL水平最低，此时LDL受体表达达到峰值。结果还表明，大鼠肝脏中的LDL受体蛋白半衰期比培养的成纤维细胞或HepG2细胞报道的半衰期短。LDL受体的最大表达发生在HMG-CoA还原酶活性峰值前数小时，并且在24小时周期内似乎不受细胞或膜胆固醇水平的影响。用地塞米松处理在节律的最低点和最高点均显著增加了LDL受体活性，但受体节律仍然维持，这表明受体表达昼夜变化的信号不是由肾上腺激素介导的。
