Impaired cholesterol metabolism and enhanced atherosclerosis in clock mutant mice.
Impaired cholesterol metabolism and enhanced atherosclerosis in clock mutant mice.
复制标题
胆固醇代谢受损并增强了时钟突变小鼠的动脉粥样硬化。
DOI：
10.1161/circulationaha.113.002885
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发表时间：
2013-10-15
期刊：
影响因子：
37.8
通讯作者：
Hussain MM
中科院分区：
文献类型：
--
作者：
Pan X;Jiang XC;Hussain MM
生物钟是一个积极控制昼夜节律调节的关键转录因子。然而，其在血浆胆固醇稳态和动脉粥样硬化中的作用尚未研究。我们首次在三种不同的小鼠模型中证明了显性负性Clock突变蛋白（ClockΔ19/Δ19）增强了血浆胆固醇和动脉粥样硬化。详细分析显示，ClkΔ19/Δ 19 Apoe −/−小鼠由于含有apoB 48的富含胆固醇酯的脂蛋白的积累而显示出高胆固醇血症。生理学研究表明，肠道对胆固醇的吸收增强会导致高胆固醇血症。分子生物学研究表明，NPC 1 L1、ACAT 2和MTP在ClkΔ19/Δ 19 Apoe −/−小鼠肠道中的表达较高，肠细胞组装并分泌更多的乳糜微粒。此外，我们确定巨噬细胞功能障碍是ClkΔ19/Δ 19 Apoe −/−小鼠动脉粥样硬化增加的另一个潜在原因。与Apoe−/−小鼠相比，ClkΔ19/Δ 19 Apoe −/−小鼠的巨噬细胞表达更高水平的清道夫受体，并摄取更多的修饰脂蛋白;但它们表达低水平的ABCA 1，并且胆固醇流出缺陷。分子研究表明，Clock通过调节USF 2的表达来调节巨噬细胞中ABCA 1的表达。ClockΔ19/Δ19蛋白通过增加肠胆固醇吸收、增加巨噬细胞对修饰的脂蛋白的摄取以及减少巨噬细胞的胆固醇流出来增强动脉粥样硬化。这些研究证实，生物钟活动在维持低血浆胆固醇水平和减少小鼠动脉粥样硬化形成方面至关重要。
Clock is a key transcription factor that positively controls circadian regulation. However, its role in plasma cholesterol homeostasis and atherosclerosis has not been studied. We show for the first time that dominant-negative Clock mutant protein (ClockΔ19/Δ19) enhances plasma cholesterol and atherosclerosis in three different mouse models. Detail analyses revealed that ClkΔ19/Δ19Apoe−/− mice display hypercholesterolemia due to the accumulation of apoB48-containing cholesteryl ester-rich lipoproteins. Physiologic studies showed that enhanced cholesterol absorption by the intestine contributes to hypercholesterolemia. Molecular studies indicated that the expression of NPC1L1, ACAT2 and MTP in the intestines of ClkΔ19/Δ19Apoe−/− mice was high and enterocytes assembled and secreted more chylomicrons. Further, we identified macrophage dysfunction as another potential cause of increased atherosclerosis in ClkΔ19/Δ19Apoe−/− mice. Macrophages from ClkΔ19/Δ19Apoe−/− mice expressed higher levels of scavenger receptors and took up more modified lipoproteins compared to Apoe−/− mice; but they expressed low levels of ABCA1 and were defective in cholesterol efflux. Molecular studies revealed that Clock regulates ABCA1 expression in macrophages by modulating USF2 expression. ClockΔ19/Δ19 protein enhances atherosclerosis by increasing intestinal cholesterol absorption, augmenting uptake of modified lipoproteins by macrophages, and reducing cholesterol efflux from macrophages. These studies establish that circadian Clock activity is crucial in maintaining low plasma cholesterol levels and in reducing atherogenesis in mice.