School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China.
Department of Occupational Health, Third Military Medical University, Chongqing, China.
J Cell Mol Med. 2019 Aug;23(8):5259-5269. doi: 10.1111/jcmm.14401. Epub 2019 May 22.
The formation of fat-laden foam cells, which contributes to the fatty streaks in the plaques of atheromas, is an important process in atherosclerosis. Vascular smooth muscle cells (VSMCs) are a critical origin of foam cells. However, the mechanisms that underlie VSMC foam cell formation are not yet completely understood. Here, we demonstrated that oxidized low-density lipoprotein (oxLDL) inhibited lipophagy by suppressing lipid droplet (LD)-lysosome fusion and increased VSMC foam cell formation. Moreover, although oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH. Notably, through TMT-based quantitative proteomic analysis and database searching, 94 differentially expressed proteins were identified, of which 54 were increased and 40 were decreased in the oxLDL group compared with those in the control group. Subsequently, SCD1, a protein of interest, was further investigated. SCD1 levels in the VSMCs were down-regulated by exposure to oxLDL in a time-dependent manner and the interaction between SCD1 and LDs was also disrupted by oxLDL. Importantly, SCD1 overexpression enhanced LD-lysosome fusion, increased lysosomal biogenesis and inhibited VSMC foam cell formation by activating TFEB nuclear translocation and its reporter activity. Modulation of the SCD1/TFEB-mediated lipophagy machinery may offer novel therapeutic approaches for the treatment of atherosclerosis.
富含脂质的泡沫细胞的形成是动脉粥样硬化斑块中脂肪条纹的重要形成过程，血管平滑肌细胞（VSMC）是泡沫细胞的重要来源。然而，VSMC 泡沫细胞形成的机制尚不完全清楚。在这里，我们证明了氧化型低密度脂蛋白（oxLDL）通过抑制脂滴（LD）-溶酶体融合来抑制脂噬，并增加 VSMC 泡沫细胞的形成。此外，尽管 oxLDL 处理抑制了溶酶体发生，但对溶酶体蛋白水解和溶酶体 pH 没有显著影响。值得注意的是，通过基于 TMT 的定量蛋白质组学分析和数据库搜索，鉴定出 94 个差异表达蛋白，其中 oxLDL 组与对照组相比，有 54 个蛋白上调，40 个蛋白下调。随后，进一步研究了 SCD1 这一感兴趣的蛋白。oxLDL 以时间依赖性方式下调 VSMC 中的 SCD1 水平，并且 oxLDL 还破坏了 SCD1 与 LD 的相互作用。重要的是，SCD1 的过表达通过激活 TFEB 核易位及其报告基因活性增强 LD-溶酶体融合，增加溶酶体发生并抑制 VSMC 泡沫细胞形成。调节 SCD1/TFEB 介导的脂噬机制可能为动脉粥样硬化的治疗提供新的治疗方法。
