Roux-en-Y gastric bypass (RYGB) has been shown to inhibit β-cell apoptosis, but the underlying mechanisms are not yet fully understood. Cytochrome c oxidase subunit 6A2 (COX6A2) is expressed in β-cells. Here, we sought to investigate the role of COX6A2 in β-cell apoptosis, especially following RYGB. We found that RYGB significantly reduced β-cell apoptosis, accompanied by decreased COX6A2 expression in islets from diabetic Goto-Kakizaki (GK) rats. It is noteworthy that overexpression of COX6A2 promoted β-cell apoptosis, whereas COX6A2 deficiency suppressed it, suggesting the pro-apoptotic role of COX6A2 in β-cells. Mechanistically, increased COX6A2 interacted with and upregulated the expression of cyclophilin D (CypD), facilitating the release of cytochrome c from mitochondria to the cytoplasm, thereby promoting β-cell apoptosis. Furthermore, high-glucose-activated ChREBP epigenetically regulated COX6A2 expression by recruiting histone acetyltransferase p300 to augment histone H3 acetylation at the Cox6a2 promoter, a process inhibited by GLP-1 signaling. Given that RYGB enhances GLP-1 signaling, RYGB is likely to deactivate ChREBP by boosting GLP-1/PKA signaling, thereby reducing COX6A2 expression in islets from GK rats. These findings highlight the crucial role of the GLP-1/PKA/ChREBP axis-controlled COX6A2 in β-cell apoptosis, revealing a previously unrecognized mechanism underlying the reduction in β-cell apoptosis induced by RYGB.

中文翻译：

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COX6A2 增加促进胰腺 β 细胞凋亡，并在 Roux-en-Y 胃旁路术后糖尿病 GK 大鼠中受到抑制


Roux-en-Y 胃旁路术 （RYGB） 已被证明可以抑制β细胞凋亡，但其潜在机制尚不完全清楚。细胞色素 c 氧化酶亚基 6A2 （COX6A2） 在 β 细胞中表达。在这里，我们试图研究 COX6A2 在 β 细胞凋亡中的作用，尤其是在 RYGB 之后。我们发现 RYGB 显着降低 β 细胞凋亡，同时降低糖尿病 Goto-Kakizaki （GK） 大鼠胰岛中 COX6A2 的表达。值得注意的是，COX6A2 的过表达促进了 β 细胞凋亡，而 COX6A2 缺陷抑制了它，表明 COX6A2 在 β 细胞中具有促凋亡作用。从机制上讲，增加的 COX6A2 与亲环蛋白 D （CypD） 的表达相互作用并上调，促进细胞色素 c 从线粒体释放到细胞质，从而促进β细胞凋亡。此外，高葡萄糖激活的 ChREBP 通过募集组蛋白乙酰转移酶 p300 来增强 Cox6a2 启动子处的组蛋白 H3 乙酰化，这一过程被 GLP-1 信号传导抑制，从而表观遗传地调节 COX6A2 表达。鉴于 RYGB 增强 GLP-1 信号传导，RYGB 可能通过增强 GLP-1/PKA 信号传导来使 ChREBP 失活，从而降低 GK 大鼠胰岛中 COX6A2 的表达。这些发现强调了 GLP-1/PKA/ChREBP 轴控制的 COX6A2 在 β 细胞凋亡中的关键作用，揭示了 RYGB 诱导的β细胞凋亡减少的先前未被认识的机制。