Department of Medical Laboratory, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Metabolism. 2021 Jan;114:154404. doi: 10.1016/j.metabol.2020.154404. Epub 2020 Oct 15.
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.
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.
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.
Our studies demonstrate that G9a plays critical roles in lipid-induced M1 macrophage polarization via negatively regulating CD36.
最近的研究认为肥胖相关的脂质环境是 2 型糖尿病中 M1 巨噬细胞极化的潜在原因。然而，具体的调节机制尚不清楚。在这里，我们研究了组蛋白甲基转移酶 G9a 在 2 型糖尿病中脂质诱导的 M1 巨噬细胞极化中的作用和分子机制。
我们使用饱和脂肪酸棕榈酸诱导巨噬细胞极化，并通过实时 PCR、western blot、流式细胞术和 CHIP 检测来研究 G9a 的功能和分子机制。此外，我们从 187 例 2 型糖尿病患者和 68 例健康个体中分离外周血单核细胞（PBMC），并分析 G9a 的表达水平。
棕榈酸处理诱导巨噬细胞 M1 极化，并降低 G9a 的表达。G9a 缺失可促进棕榈酸诱导的 M1 巨噬细胞极化，而过表达 G9a 则显著抑制这一过程。同时，我们观察到 G9a 对 ER 应激的调节作用，这可能有助于 M1 巨噬细胞。此外，我们发现 G9a 对脂肪酸转运蛋白 CD36 有调节作用。依赖于甲基转移酶活性，G9a 可负调控棕榈酸诱导的 CD36 表达。CD36 抑制剂 SSO 可显著减弱 G9a 对 M1 巨噬细胞极化和 ER 应激的调节作用。重要的是，G9a 在 2 型糖尿病患者的 PBMC 中减少，并抑制 CD36 和 M1 巨噬细胞基因的表达。
我们的研究表明，G9a 通过负调控 CD36 在脂质诱导的 M1 巨噬细胞极化中发挥关键作用。
