Mitochondrial dysfunction caused by SIRT3 inhibition drives pro-inflammatory macrophage polarization in obesity
Mitochondrial dysfunction caused by SIRT3 inhibition drives pro-inflammatory macrophage polarization in obesity
复制标题
SIRT3 抑制引起的线粒体功能障碍驱动肥胖中促炎巨噬细胞极化
作者：
Qing Zhou;Yuyan Wang;Zongshi Lu;Bowen Wang;Li Li;Mei You;Lijuan Wang;Tingbing Cao;Yu Zhao;Qiang Li;Aidi Mou;Wentao Shu;Hongbo He;Zhigang Zhao;Daoyan Liu;Zhiming Zhu;Peng Gao;Zhencheng Yan
目的代谢重编程是促炎巨噬细胞极化的一个主要特征，这是一个导致功能障碍的脂肪组织炎症的过程。因此，本研究旨在探讨线粒体脱乙酰酶sirtuin3(sirtuin3，SIRT3)是否参与了这种病理生理学process.MethodsMacrophage‐specificSirt3knockout(sirtuin3-mko)小鼠和野生型仔鼠的高脂饮食治疗。评估体重、糖耐量和炎症反应。用棕榈酸处理小鼠骨髓巨噬细胞和RAW264.7细胞，探讨SIRT3的抗炎作用机制。结果高脂饮食小鼠骨髓巨噬细胞和脂肪组织巨噬细胞中SIRT3的表达均受到明显抑制。SIRT3-MKO小鼠表现出体重增加和严重炎症，并伴有能量消耗减少和糖代谢恶化。体外实验表明，SIRT3抑制或敲除加剧了棕榈酸诱导的促炎巨噬细胞极化，而SIRT3恢复则表现出相反的作用。从机制上讲，SIRT3缺乏导致琥珀酸脱氢酶高乙酰化，导致琥珀酸蓄积，从而通过增加其启动子上的组蛋白甲基化抑制Kruppel样因子4的转录，从而激活促炎巨噬细胞。结论本研究强调了SIRT3在巨噬细胞极化中的重要预防作用，提示SIRT3是一种有前景的肥胖治疗靶点。
ObjectiveMetabolic reprogramming is a main feature of proinflammatory macrophage polarization, a process that leads to inflammation in dysfunctional adipose tissue. Therefore, the study aim was to explore whether sirtuin 3 (SIRT3), a mitochondrial deacetylase, participates in this pathophysiological process.MethodsMacrophage‐specificSirt3knockout (Sirt3‐MKO) mice and wild‐type littermates were treated with a high‐fat diet. Body weight, glucose tolerance, and inflammation were evaluated. Bone marrow–derived macrophages and RAW264.7 cells were treated with palmitic acid to explore the mechanism of SIRT3 on inflammation.ResultsThe expression of SIRT3 was significantly repressed in both bone marrow–derived macrophages and adipose tissue macrophages in mice fed with a high‐fat diet. Sirt3‐MKO mice exhibited accelerated body weight and severe inflammation, accompanied with reduced energy expenditure and worsened glucose metabolism.In vitroexperiments showed that SIRT3 inhibition or knockdown exacerbated palmitic acid–induced proinflammatory macrophage polarization, whereas SIRT3 restoration displayed opposite effects. Mechanistically, SIRT3 deficiency resulted in hyperacetylation of succinate dehydrogenase that led to succinate accumulation, which suppressed the transcription of Kruppel‐like factor 4 via increasing histone methylation on its promoter, thus evoking proinflammatory macrophages.ConclusionsThis study emphasizes an important preventive role of SIRT3 in macrophage polarization and implies that SIRT3 is a promising therapeutic target for obesity.