College of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China; Hebei Key Laboratory for Chronic Diseases, College of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China.
Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China.
J Nutr Biochem. 2022 Sep;107:109060. doi: 10.1016/j.jnutbio.2022.109060. Epub 2022 May 25.
Quercetin, a natural flavonoid, has been reported to prevent pancreatic β-cell apoptosis in animal models of diabetes. However, the underlying mechanism remains unclear. We investigated the mechanisms through which quercetin protects β cells from palmitate-induced apoptosis and determined whether autophagy is involved in this process. We found that quercetin treatment partially reduced palmitate-induced β-cell apoptosis. This protective effect was abolished by pharmacologic inhibition of autophagy and by silencing a key autophagy gene. Further analysis revealed that palmitate treatment promoted the expression of LC3 II, a marker of autophagosomes, but resulted in the blockade of autophagic flux due to lysosome dysfunction. Defective lysosome accumulation can cause lysosomal membrane permeabilization and the release of cathepsins from lysosome into the cytosol that triggers apoptosis. Treatment with quercetin reversed lysosomal dysfunction and promoted autophagosome-lysosome fusion, which restored defective autophagic flux and provoked autophagy. Overall, our results indicate that lysosomal dysfunction is a major factor that contributes to β-cell apoptosis and demonstrates that quercetin improves cell survival by restoring lysosomal function and autophagic flux. This study provides new evidence regarding the anti-apoptotic mechanism of quercetin in the treatment of type 2 diabetes.
槲皮素是一种天然类黄酮，据报道它可以预防糖尿病动物模型中的胰岛β细胞凋亡。然而，其潜在的作用机制尚不清楚。我们研究了槲皮素保护β细胞免受棕榈酸诱导的凋亡的机制，并确定自噬是否参与这一过程。我们发现，槲皮素治疗部分减少了棕榈酸诱导的β细胞凋亡。自噬的药理学抑制和关键自噬基因的沉默消除了这种保护作用。进一步的分析表明，棕榈酸处理促进了自噬体 LC3 II 的表达，但由于溶酶体功能障碍导致自噬流阻断。溶酶体功能障碍会导致溶酶体积累缺陷，从而导致溶酶体膜通透性增加，以及组织蛋白酶从溶酶体释放到细胞质中，引发细胞凋亡。槲皮素处理逆转了溶酶体功能障碍，促进了自噬体-溶酶体融合，恢复了有缺陷的自噬流并引发了自噬。总的来说，我们的结果表明溶酶体功能障碍是β细胞凋亡的一个主要因素，并表明槲皮素通过恢复溶酶体功能和自噬流来提高细胞存活率。这项研究为槲皮素在 2 型糖尿病治疗中的抗细胞凋亡机制提供了新的证据。
