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Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation
Cell Reports ( IF 7.5 ) Pub Date : 2024-05-10 , DOI: 10.1016/j.celrep.2024.114180
Yunjia Zhang 1 , Hong Jiang 2 , Mengdie Dong 2 , Jiao Min 2 , Xian He 2 , Yongkang Tan 2 , Fuhao Liu 3 , Minghong Chen 2 , Xiang Chen 2 , Quanwen Yin 2 , Longbin Zheng 4 , Yongfeng Shao 5 , Xuesong Li 2 , Hongshan Chen 6
Cell Reports ( IF 7.5 ) Pub Date : 2024-05-10 , DOI: 10.1016/j.celrep.2024.114180
Yunjia Zhang 1 , Hong Jiang 2 , Mengdie Dong 2 , Jiao Min 2 , Xian He 2 , Yongkang Tan 2 , Fuhao Liu 3 , Minghong Chen 2 , Xiang Chen 2 , Quanwen Yin 2 , Longbin Zheng 4 , Yongfeng Shao 5 , Xuesong Li 2 , Hongshan Chen 6
Affiliation
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Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.
中文翻译：
巨噬细胞 MCT4 抑制激活修复基因并通过组蛋白 H3 赖氨酸 18 乳酸化防止动脉粥样硬化
巨噬细胞活化是动脉粥样硬化的标志，伴随着核心代谢从氧化磷酸化转变为糖酵解。巨噬细胞中代谢重新布线和组蛋白修饰之间的串扰值得进一步研究。在这里，我们发现乳酸外排相关的单羧酸转运蛋白 4 （MCT4） 介导的组蛋白乳酸化与动脉粥样硬化密切相关。依赖于 MCT4 缺陷的组蛋白 H3 赖氨酸 18 乳酰化激活了抗炎基因和三羧酸循环基因的转录，导致局部修复和体内平衡的启动。引人注目的是，组蛋白乳酸化特征性地参与 M1 到 M2 转化过程中的阶段特异性局部修复过程，而组蛋白甲基化和乙酰化则不然。基因作和蛋白质水解靶向嵌合体技术用于确认 MCT4 缺陷有利于改善动脉粥样硬化。因此，我们的研究表明，巨噬细胞 MCT4 缺乏症将代谢重新布线和组蛋白修饰联系起来，在训练巨噬细胞成为修复和稳态表型方面起着关键作用。
更新日期：2024-05-10
中文翻译：
巨噬细胞 MCT4 抑制激活修复基因并通过组蛋白 H3 赖氨酸 18 乳酸化防止动脉粥样硬化
巨噬细胞活化是动脉粥样硬化的标志，伴随着核心代谢从氧化磷酸化转变为糖酵解。巨噬细胞中代谢重新布线和组蛋白修饰之间的串扰值得进一步研究。在这里，我们发现乳酸外排相关的单羧酸转运蛋白 4 （MCT4） 介导的组蛋白乳酸化与动脉粥样硬化密切相关。依赖于 MCT4 缺陷的组蛋白 H3 赖氨酸 18 乳酰化激活了抗炎基因和三羧酸循环基因的转录，导致局部修复和体内平衡的启动。引人注目的是，组蛋白乳酸化特征性地参与 M1 到 M2 转化过程中的阶段特异性局部修复过程，而组蛋白甲基化和乙酰化则不然。基因作和蛋白质水解靶向嵌合体技术用于确认 MCT4 缺陷有利于改善动脉粥样硬化。因此，我们的研究表明，巨噬细胞 MCT4 缺乏症将代谢重新布线和组蛋白修饰联系起来，在训练巨噬细胞成为修复和稳态表型方面起着关键作用。
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