C1q/tumor necrosis factor‐related protein‐6 attenuates TNF‐α‐induced apoptosis in salivary acinar cells via AMPK/SIRT1‐modulated miR‐34a‐5p expression,Journal of Cellular Physiology

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C1q/tumor necrosis factor‐related protein‐6 attenuates TNF‐α‐induced apoptosis in salivary acinar cells via AMPK/SIRT1‐modulated miR‐34a‐5p expression
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-05 , DOI: 10.1002/jcp.30262
Ling-Han Qu ₁ , Xia Hong ₂ , Yan Zhang ₃ , Xin Cong ₃ , Ruo-Lan Xiang ₃ , Mei Mei ₄ , Jia-Zeng Su ₁ , Li-Ling Wu ₃ , Guang-Yan Yu ₁

Affiliation

C1q/tumor necrosis factor‐related protein‐6 (CTRP6) is a newly identified adipokine involved in diverse biological processes. However, its role in salivary glands remains unknown. Here, we demonstrated that CTRP6 was mainly distributed in the nuclei, apicolateral membranes, and cytoplasm of human submandibular glands (SMGs), serous cells of parotid glands, and ducts and apicolateral membranes of serous cells in rats and mice. CTRP6 inhibited the apoptosis rate and reversed the increased levels of cleaved caspase 3, caspase 8, caspase 9, and cytochrome C and the decreased Bcl‐2 expression induced by tumor necrosis factor (TNF)‐α in both SMG‐C6 cells and cultured human SMG tissues. Microarray analysis identified 43 differentially expressed microRNAs (miRNAs) in the SMGs of nonobese diabetic mice. miR‐34a‐5p was selected due to its upregulation by TNF‐α, which was abolished by CTRP6. The miR‐34a‐5p inhibitor promoted whereas the miR‐34a‐5p mimic suppressed the effects of CTRP6 on TNF‐α‐induced apoptosis. CTRP6 increased AMP‐activated protein kinase (AMPK) phosphorylation and reversed TNF‐α‐induced SIRT1 downregulation in salivary cells. AraA, an AMPK inhibitor, reversed the effects of CTRP6 on TNF‐α‐induced alterations in the levels of SIRT1, miR‐34a‐5p, Bcl‐2, and cleaved caspase 3 in vitro and ex vivo, whereas activating AMPK by AICAR reversed the decrease in SIRT1 expression and increase in miR‐34a‐5p expression induced by TNF‐α. Inhibition of SIRT1 by EX527 suppressed the effects of CTRP6 on TNF‐α‐induced changes in miR‐34a‐5p and apoptosis‐related proteins. Our findings indicate that salivary glands are novel sites for CTRP6 synthesis and secretion. CTRP6 protects acinar cells against TNF‐α‐induced apoptosis via AMPK/SIRT1‐modulated miR‐34a‐5p expression.

中文翻译：

C1q/肿瘤坏死因子相关蛋白-6 通过 AMPK/SIRT1 调节的 miR-34a-5p 表达减弱 TNF-α 诱导的唾液腺细胞凋亡

C1q/肿瘤坏死因子相关蛋白 6 (CTRP6) 是一种新发现的脂肪因子，参与多种生物过程。然而，它在唾液腺中的作用仍然未知。在这里，我们证明了 CTRP6 主要分布在人下颌下腺 (SMG) 的细胞核、顶外侧膜和细胞质、腮腺的浆液细胞以及大鼠和小鼠的浆液细胞的导管和顶外侧膜中。CTRP6 抑制细胞凋亡率并逆转 SMG-C6 细胞和培养的人细胞中裂解的 caspase 3、caspase 8、caspase 9 和细胞色素 C 的水平升高以及肿瘤坏死因子 (TNF)-α 诱导的 Bcl-2 表达降低SMG 组织。微阵列分析在非肥胖糖尿病小鼠的 SMG 中鉴定出 43 种差异表达的 microRNA (miRNA)。选择 miR-34a-5p 是因为它被 TNF-α 上调，而 TNF-α 被 CTRP6 消除。miR-34a-5p 抑制剂促进而 miR-34a-5p 模拟物抑制 CTRP6 对 TNF-α 诱导的细胞凋亡的影响。CTRP6 增加 AMP 活化蛋白激酶 (AMPK) 磷酸化并逆转唾液细胞中 TNF-α 诱导的 SIRT1 下调。AMPK 抑制剂 AraA 在体外和离体中逆转了 CTRP6 对 TNF-α 诱导的 SIRT1、miR-34a-5p、Bcl-2 和裂解的 caspase 3 水平变化的影响，而通过 AICAR 激活 AMPK 逆转了TNF-α诱导的SIRT1表达降低和miR-34a-5p表达增加。EX527 对 SIRT1 的抑制抑制了 CTRP6 对 TNF-α 诱导的 miR-34a-5p 和细胞凋亡相关蛋白变化的影响。我们的研究结果表明唾液腺是 CTRP6 合成和分泌的新位点。CTRP6 通过 AMPK/SIRT1 调节的 miR-34a-5p 表达保护腺泡细胞免受 TNF-α 诱导的细胞凋亡。

更新日期：2021-01-05

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