Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages.
Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages.
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脂肪细胞脂肪酸结合蛋白促进棕榈酸诱导的巨噬细胞线粒体功能障碍和细胞凋亡
DOI：
10.3389/fimmu.2018.00081
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发表时间：
2018
影响因子：
7.3
通讯作者：
Zhou ZG
中科院分区：
文献类型：
--
作者：
Li H;Xiao Y;Tang L;Zhong F;Huang G;Xu JM;Xu AM;Dai RP;Zhou ZG
众所周知，高水平的循环游离脂肪酸（FFA）是动脉粥样硬化发展过程中巨噬细胞凋亡的重要触发因素。然而，FFA 导致巨噬细胞凋亡的潜在机制尚不清楚。在培养的人巨噬细胞Thp-1细胞中，我们发现循环中最丰富的FFA棕榈酸（PA）会诱导过量的反应性氧化物质产生，增加丙二醛浓度，并降低三磷酸腺苷水平。此外，PA治疗还导致线粒体功能障碍，包括线粒体数量减少、呼吸复合物IV和琥珀酸脱氢酶活性受损以及线粒体膜电位降低。 PA 处理后还检测到线粒体凋亡，表现为细胞色素 c 释放减少、Bcl-2 下调、Bax 上调和 caspase-3 活性增加。 PA 治疗上调了脂肪细胞脂肪酸结合蛋白 (A-FABP) 的表达，该蛋白是脂肪酸运输和脂质代谢的关键调节因子。小分子A-FABP抑制剂BMS309403对A-FABP的抑制几乎逆转了所有这些指标。因此，这项研究表明 PA 通过上调 A-FABP 介导巨噬细胞凋亡，从而导致线粒体功能障碍和反应性氧化应激。抑制 A-FABP 可能是巨噬细胞凋亡和延缓动脉粥样硬化进展的潜在治疗靶点。
A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis.