Burgess Braydon, Naus Kathryn, Chan Jeniffer, Hirsch-Reinshagen Veronica, Tansley Gavin, Matzke Lisa, Chan Benny, Wilkinson Anna, Fan Jianjia, Donkin James, Balik Danielle, Tanaka Tracie, Ou George, Dyer Roger, Innis Sheila, McManus Bruce, Lütjohann Dieter, Wellington Cheryl
Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1731-7. doi: 10.1161/ATVBAHA.108.168542. Epub 2008 Jul 3.
The purpose of this study was to evaluate the effects of whole body overexpression of human ABCG1 on atherosclerosis in apoE(-/-) mice.
We generated BAC transgenic mice in which human ABCG1 is expressed from endogenous regulatory signals, leading to a 3- to 7-fold increase in ABCG1 protein across various tissues. Although the ABCG1 BAC transgene rescued lung lipid accumulation in ABCG1(-/-) mice, it did not affect plasma lipid levels, macrophage cholesterol efflux to HDL, atherosclerotic lesion area in apoE(-/-) mice, or levels of tissue cholesterol, cholesterol ester, phospholipids, or triglycerides. Subtle changes in sterol biosynthetic intermediate levels were observed in liver, with chow-fed ABCG1 BAC Tg mice showing a nonsignificant trend toward decreased levels of lathosterol, lanosterol, and desmosterol, and fat-fed mice exhibiting significantly elevated levels of each intermediate. These changes were insufficient to alter ABCA1 expression in liver.
Transgenic human ABCG1 does not influence atherosclerosis in apoE(-/-) mice but may participate in the regulation of tissue cholesterol biosynthesis.
本研究旨在评估人ABCG1在全身过表达对载脂蛋白E基因敲除（apoE(-/-)）小鼠动脉粥样硬化的影响。
我们构建了BAC转基因小鼠，其中人ABCG1由内源性调控信号表达，导致各组织中ABCG1蛋白增加3至7倍。尽管ABCG1 BAC转基因挽救了ABCG1基因敲除小鼠肺部的脂质蓄积，但它不影响血浆脂质水平、巨噬细胞胆固醇向高密度脂蛋白（HDL）的流出、apoE(-/-)小鼠的动脉粥样硬化病变面积，或组织胆固醇、胆固醇酯、磷脂或甘油三酯的水平。在肝脏中观察到固醇生物合成中间产物水平有细微变化，正常饮食喂养的ABCG1 BAC转基因小鼠显示羊毛甾醇、羊毛脂甾醇和去氢胆固醇水平有不显著的下降趋势，高脂喂养的小鼠则显示每种中间产物水平显著升高。这些变化不足以改变肝脏中ABCA1的表达。
转基因人ABCG1不影响apoE(-/-)小鼠的动脉粥样硬化，但可能参与组织胆固醇生物合成的调节。
