Background

Recent studies have considered the obesity-related lipid environment as the potential cause for M1 macrophage polarization in type 2 diabetes. However, the specific regulatory mechanism is still unclear. Here, we investigated the role and molecular mechanism of histone methyltransferases G9a in lipids-induced M1 macrophage polarization in type 2 diabetes.

Methods

We used saturated fatty acid palmitate to induce macrophage polarization, and performed real-time PCR, western blot, flow cytometry and CHIP assay to study the function and molecular mechanism of G9a. Additionally, we isolated the peripheral blood mononuclear cells (PBMCs) from 187 patients with type 2 diabetes and 68 healthy individuals, and analyzed the expression level of G9a.

Results

The palmitate treatment induced the macrophage M1 polarization, and decreased the expression of G9a. The deficiency of G9a could promote the palmitate-induced M1 macrophage polarization, whereas, over-expressing G9a notably suppressed this process. Meanwhile, we observed the regulatory role of G9a on the ER stress which could contribute to M1 macrophage. Furthermore, we identified the fatty acid transport protein CD36 as the potential target of G9a. Dependent on the methyltransferase activity, G9a could negatively regulate the expression of CD36 induced by palmitate. The CD36 inhibitor SSO could significantly attenuate the regulatory effect of G9a on M1 macrophage polarization and ER stress. Importantly, G9a was decreased, and suppressed CD36 and M1 macrophage genes in the PBMCs from individuals with type 2 diabetes.

Conclusions

Our studies demonstrate that G9a plays critical roles in lipid-induced M1 macrophage polarization via negatively regulating CD36.

中文翻译：

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组蛋白甲基转移酶G9a通过负调节CD36介导脂质诱导的M1巨噬细胞极化。

背景

最近的研究已将肥胖相关的脂质环境视为2型糖尿病中M1巨噬细胞极化的潜在原因。但是，具体的监管机制仍不清楚。在这里，我们调查了组蛋白甲基转移酶G9a在2型糖尿病脂质诱导的M1巨噬细胞极化中的作用和分子机制。

方法

我们使用饱和脂肪酸棕榈酸酯诱导巨噬细胞极化，并进行实时PCR，蛋白质印迹，流式细胞术和CHIP分析，以研究G9a的功能和分子机制。此外，我们从187位2型糖尿病患者和68位健康个体中分离了外周血单核细胞（PBMC），并分析了G9a的表达水平。

结果

棕榈酸酯处理可诱导巨噬细胞M1极化，并降低G9a的表达。G9a的缺乏可能促进棕榈酸酯诱导的M1巨噬细胞极化，而过表达G9a则明显抑制了这一过程。同时，我们观察到G9a对内质网应激的调节作用，这可能有助于M1巨噬细胞。此外，我们确定了脂肪酸转运蛋白CD36为G9a的潜在目标。依赖于甲基转移酶活性，G9a可以负调控棕榈酸酯诱导的CD36的表达。CD36抑制剂SSO可以显着减弱G9a对M1巨噬细胞极化和内质网应激的调节作用。重要的是，G9a减少并抑制了2型糖尿病患者PBMC中的CD36和M1巨噬细胞基因。

结论

我们的研究表明，G9a通过负调节CD36在脂质诱导的M1巨噬细胞极化中起关键作用。