Department of endocrinology, Institute of geriatric medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
Department of laboratory medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
Autophagy. 2020 Jun;16(6):1111-1129. doi: 10.1080/15548627.2019.1659613. Epub 2019 Sep 4.
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.
3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A; 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.
糖尿病是动脉粥样硬化发展的公认高危因素，其中巨自噬/自噬正在发挥重要作用。低密度脂蛋白（LDL）颗粒经跨内皮细胞转运后保留在内皮下空间是动脉粥样硬化的初始步骤。在这里，我们发现高葡萄糖可以通过刺激 LDL 的跨细胞转运来促进动脉粥样硬化。通过抑制 AMPK-MTOR-PIK3C3 途径，高葡萄糖抑制 CAV-CAVIN-LC3B 介导的 CAV1 的自噬降解；因此，更多的 CAV1 积累在细胞质中，并用于在细胞膜上形成更多的 caveolae，从而促进 LDL 跨内皮细胞转运。作为概念验证，与没有 GDM 的孕妇相比，患有妊娠糖尿病（GDM）的孕妇脐静脉壁的内皮下空间中积累了更高水平的脂质。我们的结果表明，高葡萄糖通过一种新型的 CAV1-CAVIN1-LC3B 信号转导介导的自噬降解途径刺激 LDL 跨细胞转运。
3-MA：3-甲基腺嘌呤；ACTB：肌动蛋白β；AMPK：AMP 激活的蛋白激酶；Bafi：巴佛霉素 A；CAV1：窖蛋白-1；CAVIN1：小窝相关蛋白 1；CSD：CAV1 支架结构域；GDM：妊娠糖尿病；IMD：跨膜结构域；LIR：LC3 相互作用区域；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MFI：平均荧光强度；MTOR：雷帕霉素机制靶蛋白激酶；PIK3C3/VPS34：磷脂酰肌醇 3-激酶催化亚单位 3；SQSTM1/p62：自噬相关蛋白 1。
