LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages.
LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages.
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DOI：
10.1371/journal.pone.0128903
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Strickland DK
中科院分区：
文献类型：
--
作者：
Lillis AP;Muratoglu SC;Au DT;Migliorini M;Lee MJ;Fried SK;Mikhailenko I;Strickland DK
在循环中，胆固醇由脂蛋白颗粒运输，当这些颗粒与细胞受体结合时，胆固醇被细胞吸收。在巨噬细胞中，过量的脂蛋白颗粒摄取导致泡沫细胞形成，这是动脉粥样硬化发展的早期事件。目前，泡沫泡孔形成的机制还不完全清楚。迄今为止，已经鉴定了几种巨噬细胞受体，其有助于吸收修饰形式的脂蛋白，导致泡沫细胞形成，但LDL受体相关蛋白1（LRP 1）对该过程的贡献尚不清楚。为了研究LRP 1在巨噬细胞胆固醇蓄积中的作用，我们在LDL受体（LDLR）缺陷背景（macLRP 1-/-）的巨噬细胞中产生了选择性缺失LRP 1的小鼠。在给小鼠喂食高脂饮食11周后，从Lrp +/+小鼠分离的腹腔巨噬细胞的总胆固醇水平显著高于macLRP 1-/-小鼠。进一步的分析表明，这是由于胆固醇酯水平增加。有趣的是，macLRP 1-/-小鼠显示血浆胆固醇和甘油三酯水平升高，这是由于循环中富含脂蛋白的大脂蛋白颗粒的积累。这种增加不是由于肝脏VLDL生物合成的增加，而是由于macLRP 1-/-小鼠中富含磷脂酰肌醇的脂蛋白颗粒的催化缺陷。这些研究揭示了巨噬细胞LRP 1对胆固醇稳态的重要体内贡献。
Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the contribution of the LDL receptor-related protein 1 (LRP1) to this process is not known. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR)-deficient background (macLRP1-/-). After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp +/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis.
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影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J
DOI：
10.1016/0006-291x(85)90117-2
发表时间：
1985-01-01
影响因子：
3.1
作者：
FELDMAN, SR;ROSENBERG, MR;PIZZO, SV
通讯作者：
PIZZO, SV
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
影响因子：
15.9
作者：
Febbraio, M;Podrez, EA;Silverstein, RL
通讯作者：
Silverstein, RL