COX6A2 增加会促进胰腺 β 细胞凋亡，并在糖尿病 GK 大鼠接受 Roux-en-Y 胃旁路术后受到抑制。

Diabetes Pub Date : 2025-02-01 DOI:10.2337/db24-0301

Xiangchen Kong, Dan Yan, Lianqi Shao, Bingfeng Li, Simian Lv, Yifan Tu, Yingqi Zhang, Xingsheng Shu, Ying Ying, Xiaosong Ma

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引用次数: 0

摘要

研究表明，Roux-en-Y 胃旁路术（RYGB）可抑制β细胞凋亡，但其基本机制尚未完全明了。细胞色素 c 氧化酶亚基 6A2（COX6A2）在β细胞中表达。在此，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，在糖尿病 Goto-Kakizaki （GK）大鼠的胰岛中，RYGB 能明显减少 β 细胞凋亡，同时 COX6A2 的表达也减少了。值得注意的是，过量表达 COX6A2 会促进 β 细胞凋亡，而 COX6A2 缺乏则会抑制 β 细胞凋亡，这表明 COX6A2 在 β 细胞中具有促凋亡作用。从机制上讲，COX6A2的增加与环嗜蛋白D（CypD）相互作用并上调其表达，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 通过招募组蛋白乙酰转移酶 p300 来增强 Cox6a2 启动子上的组蛋白 H3 乙酰化，从而对 COX6A2 的表达进行表观遗传调控，而这一过程会受到 GLP-1 信号的抑制。鉴于 RYGB 可增强 GLP-1 信号传导，RYGB 很可能会通过增强 GLP-1/PKA 信号传导使 ChREBP 失活，从而减少 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 细胞凋亡减少的一个以前未被认识的机制。

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Increased COX6A2 Promotes Pancreatic β-Cell Apoptosis and Is Suppressed in Diabetic GK Rats After Roux-en-Y Gastric Bypass.

Article highlights: Cytochrome c oxidase subunit 6A2 (COX6A2) expression is increased in diabetic islets. Increased COX6A2 promotes β-cell apoptosis via modulation of cyclophilin D-mediated cytochrome c release from mitochondria to the cytoplasm. Carbohydrate-responsive element-binding protein epigenetically regulates COX6A2 expression in β-cells. Roux-en-Y gastric bypass reduces COX6A2 expression by regulating the glucagon-like peptide 1/cAMP-dependent protein kinase/carbohydrate-responsive element-binding protein signaling pathway.

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Diabetes

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