Departments of Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
McGuire Veterans Affairs Medical Center, Richmond, VA 23248.
J Lipid Res. 2019 Jun;60(6):1087-1098. doi: 10.1194/jlr.M091967. Epub 2019 Apr 23.
How plasma membrane (PM) cholesterol is controlled is poorly understood. Ablation of the gene encoding the ER stress steroidogenic acute regulatory-related lipid transfer domain (StarD)5 leads to a decrease in PM cholesterol content, a decrease in cholesterol efflux, and an increase in intracellular neutral lipid accumulation in macrophages, the major cell type that expresses StarD5. ER stress increases StarD5 expression in mouse hepatocytes, which results in an increase in accessible PM cholesterol in WT but not in StarD5 hepatocytes. StarD5 mice store higher levels of cholesterol and triglycerides, which leads to altered expression of cholesterol-regulated genes. In vitro, a recombinant GST-StarD5 protein transfers cholesterol between synthetic liposomes. StarD5 overexpression leads to a marked increase in PM cholesterol. Phasor analysis of 6-dodecanoyl-2-dimethylaminonaphthalene fluorescence lifetime imaging microscopy data revealed an increase in PM fluidity in StarD5 macrophages. Taken together, these studies show that StarD5 is a stress-responsive protein that regulates PM cholesterol and intracellular cholesterol homeostasis.
目前人们对质膜（PM）胆固醇的调控机制知之甚少。编码内质网应激类固醇生成急性调节相关脂转移结构域（StarD）5 的基因缺失会导致 PM 胆固醇含量降低、胆固醇外排减少以及巨噬细胞（主要表达 StarD5 的细胞类型）内中性脂质积累增加。内质网应激会增加小鼠肝细胞中 StarD5 的表达，导致 WT 细胞中 PM 胆固醇的可及性增加，但 StarD5 肝细胞中则没有。StarD5 小鼠储存了更高水平的胆固醇和甘油三酯，这导致了胆固醇调节基因的表达改变。在体外，重组 GST-StarD5 蛋白在合成脂质体之间转移胆固醇。StarD5 的过表达导致 PM 胆固醇显著增加。6-十二烷酰-2-二甲基氨基萘荧光寿命成像显微镜数据的相分析显示，StarD5 巨噬细胞中 PM 的流动性增加。综上所述，这些研究表明 StarD5 是一种应激反应蛋白，可调节 PM 胆固醇和细胞内胆固醇稳态。
