TIGAR 通过促进巨噬细胞内胆固醇外流来减轻动脉粥样硬化。
TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages.
机构信息
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China.
出版信息
Atherosclerosis. 2021 Jun;327:76-86. doi: 10.1016/j.atherosclerosis.2021.04.002. Epub 2021 Apr 20.
BACKGROUND AND AIMS
TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism.
METHODS
The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe) mice were used as an in vivo model. [H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC).
RESULTS
Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe mice.
CONCLUSIONS
TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway.
背景与目的
TP53 诱导的糖酵解和凋亡调节剂（TIGAR）现已被确定为果糖-2,6-二磷酸酶，可降低糖酵解并抵抗氧化应激。最近的研究表明，TIGAR 与心血管疾病有关。然而，其在动脉粥样硬化形成中的作用知之甚少。本研究旨在探讨 TIGAR 对动脉粥样硬化的影响，并探讨其潜在的分子机制。
方法
使用基因表达综合数据库（GEO）数据集分析相对蛋白的差异表达。使用 THP-1 衍生的巨噬细胞作为体外模型，使用载脂蛋白 E 缺陷（Apoe）小鼠作为体内模型。使用[H]标记的胆固醇评估胆固醇流出和胆固醇逆向转运（RCT）的能力。分别使用 qPCR 和 Western blot 评估 mRNA 和蛋白表达。使用慢病毒载体干扰体外和体内 TIGAR 的表达。用西方饮食喂养 Apoe 小鼠，用油红 O、苏木精-伊红和 Masson 染色评估动脉粥样硬化斑块。使用常规测定试剂盒测量活性氧（ROS）、血浆脂质谱和 27-羟胆固醇（27-HC）的水平。
结果
结果表明，TIGAR 在巨噬细胞泡沫细胞形成和动脉粥样硬化时增加。TIGAR 敲低显著促进巨噬细胞中的脂质积累。沉默 TIGAR 通过干扰肝 X 受体 α（LXRα）表达和活性，损害胆固醇流出并下调 ATP 结合盒转运体 A1（ABCA1）和 ABCG1 的表达，但不影响巨噬细胞摄取胆固醇。此外，TIGAR 缺乏对胆固醇代谢的这种抑制作用是通过 ROS/CYP27A1 途径介导的。体内实验表明，TIGAR 缺乏降低斑块和主动脉中 ABCA1 和 ABCG1 的水平，并损害 RCT 能力，从而导致 Apoe 小鼠动脉粥样硬化的进展。
结论
TIGAR 通过 ROS/CYP27A1/LXRα 途径上调 ABCA1 和 ABCG1 的表达，减轻动脉粥样硬化的发展。
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