CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis
CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis
复制标题
CAV1-CAVIN1-LC3B介导的自噬调节高葡萄糖刺激的LDL转胞吞作用
DOI：
10.1080/15548627.2019.1659613
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发表时间：
2019-09-06
期刊：
影响因子：
13.3
通讯作者：
Jin, Si
中科院分区：
文献类型：
--
作者：
Bai, Xiangli;Yang, Xiaoyan;Jin, Si
糖尿病是公认的动脉粥样硬化发展的高危因素，其中巨噬/自噬正在发挥重要作用。低密度脂蛋白（LDL）颗粒在内皮细胞胞吞作用后滞留在内皮下空间是动脉粥样硬化的第一步。在这里，我们发现高葡萄糖可以通过刺激LDL的胞吞作用来促进动脉粥样硬化。高糖通过抑制AMPK-MTOR-PIK3C3通路，抑制cav - cavin - lc3b介导的CAV1自噬降解；因此，更多的CAV1积聚在细胞质中，并被利用在细胞膜上形成更多的小泡，促进LDL跨内皮细胞的胞吞作用。为了证明这一概念，与没有妊娠糖尿病的孕妇相比，妊娠糖尿病（GDM）孕妇在脐静脉壁内皮下空间中积累了更高水平的脂质。我们的研究结果表明，高葡萄糖通过一种新的cav1 - cavin - lc3b信号介导的自噬降解途径刺激LDL胞吞。缩写3-MA: 3-甲基腺嘌呤；ACTB：肌动蛋白；AMPK: amp活化蛋白激酶；Bafi：巴菲霉素A1；CAV1: caveolin-1;CAVIN1：小泡相关蛋白1；CSD: CAV1脚手架结构域；GDM：妊娠期糖尿病；IMD：膜内域；LIR: lc3相互作用区；MAP1LC3/LC3：微管相关蛋白1轻链3；MFI：平均荧光强度；MTOR：雷帕霉素激酶的机制靶点PIK3C3/VPS34：磷脂酰肌醇3-激酶催化亚基3；SQSTM1/p62: sequestosome
ABSTRACT Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. Abbreviations 3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A1; CAV1: caveolin-1; CAVIN1: caveolae associated protein 1; CSD: the CAV1 scaffolding domain; GDM: gestational diabetes mellitus; IMD: intramembrane domain; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule- associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTOR: mechanistic target of rapamycin kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; SQSTM1/p62: sequestosome 1.