Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene
Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene
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DOI：
10.1074/jbc.274.4.2366
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Tall, AR
中科院分区：
文献类型：
--
作者：
Arai, T;Wang, N;Tall, AR
B 类 I 型清道夫受体 (SR-BI) 最初被鉴定为识别低密度脂蛋白 (LDL) 的受体，最近显示可介导肝脏和类固醇生成组织中高密度脂蛋白 (HDL) 胆固醇酯的选择性摄取。为了评估对动脉粥样硬化的影响，将肝脏特异性过度表达 SR-BI 的转基因小鼠（SR-BI Tg 小鼠）与 LDL 受体缺陷的背景进行杂交，为了在中度高胆固醇血症的环境中诱导动脉粥样硬化，杂合 LDL 受体缺陷小鼠 (LDLR1) 被喂食高脂肪/胆固醇/胆盐饮食，纯合 LDL 受体敲除小鼠 (LDLR0) 被喂食高脂肪/胆固醇饮食。与 LDLR1 小鼠相比，LDLR1/SRBI Tg 小鼠的 VLDL、LDL 和 HDL 胆固醇降低，主动脉根平均病变面积显着减少 80%（雌性 LDLR1 74, 120 μ m(2) 对比 LDLR1/SR-BI Tg 12, 667 μ m(2)；雄性 25, 747 μm(2) 对比 5, 448分别为μ m(2))。与LDLR0小鼠相比，LDLR0/SR-BI Tg小鼠的LDL和HDL胆固醇降低，但VLDL胆固醇升高，且动脉粥样硬化程度无显着差异。综合数据分析显示，动脉粥样硬化病变面积与VLDL+LDL胆固醇水平有很强的相关性，但与HDL水平没有相关性。这些研究表明，肝脏 SR-BI 过度表达具有强大的抗动脉粥样硬化潜力。在 SR-BI 明显过度表达的小鼠中，保护作用似乎主要与 VLDL 和 LDL 胆固醇水平的降低有关。
Scavenger receptor type B class I (SR-BI), initially identified as a receptor that recognizes low density lipoprotein (LDL), was recently shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters in liver and steroidogenic tissues. To evaluate effects on atherosclerosis, transgenic mice with liver-specific overexpression of SR-BI (SR-BI Tg mice) have been crossed onto LDL receptor-deficient backgrounds, To induce atherosclerosis in a setting of moderate hypercholesterolemia, heterozygous LDL receptor-deficient mice (LDLR1) were fed a high fat/cholesterol/bile salt diet, and homozygous LDL receptor knock-outs (LDLR0) were fed a high fat/cholesterol diet. LDLR1/SRBI Tg mice showed decreases in VLDL, LDL, and HDL cholesterol and a significant 80% decrease in mean lesion area in the aortic root compared with LDLR1 mice (female LDLR1 74, 120 mu m(2) versus LDLR1/SR-BI Tg 12, 667 mu m(2); male 25, 747 mu m(2) versus 5, 448 mu m(2), respectively). LDLR0/SR-BI Tg mice showed decreased LDL and HDL cholesterol but increased VLDL cholesterol and no significant difference in extent of atherosclerosis compared with LDLR0 mice. Combined data analysis showed a strong correlation between atherosclerotic lesion area and the VLDL+LDL cholesterol level but no correlation with HDL level. These studies demonstrate a strong anti-atherogenic potential of hepatic SR-BI overexpression, In mice with marked over-expression of SR-BI, the protective effect appears to be primarily related to the lowering of VLDL and LDL cholesterol levels.