C1q/tumor necrosis factor-related protein-6 attenuates TNF-α-induced apoptosis in salivary acinar cells via AMPK/SIRT1-modulated miR-34a-5p expression
C1q/tumor necrosis factor-related protein-6 attenuates TNF-α-induced apoptosis in salivary acinar cells via AMPK/SIRT1-modulated miR-34a-5p expression
复制标题
C1q/肿瘤坏死因子相关蛋白-6 通过 AMPK/SIRT1 调节 miR-34a-5p 表达减弱 TNF-α 诱导的唾液腺泡细胞凋亡
DOI：
10.1002/jcp.30262
复制
发表时间：
2021-01-05
影响因子：
5.6
通讯作者：
Yu, Guang-Yan
中科院分区：
文献类型：
--
作者：
Qu, Ling-Han;Hong, Xia;Yu, Guang-Yan
C1q/肿瘤坏死因子相关蛋白-6(CTRP6)是新近发现的一种参与多种生物学过程的脂肪因子。然而，它在唾液腺中的作用仍不清楚。在此，我们证明了CTRP6主要分布于人颌下腺(SMGs)的细胞核、顶侧膜和细胞质，腮腺的浆液性细胞，以及大鼠和小鼠的浆液性细胞的导管和顶侧膜。CTRP6可抑制肿瘤坏死因子-α诱导的SMG-C6细胞和人SMG组织中caspase3、caspase8、caspase9和细胞色素C的表达增加和bcl2表达的降低，并抑制细胞凋亡率。微阵列分析在非肥胖糖尿病小鼠的SMG中鉴定出43个差异表达的microRNAs(MiRNAs)。之所以选择mir-34a-5p，是因为它被肿瘤坏死因子-α上调，但被CTRP6取消。MiR-34a-5p抑制剂促进肿瘤坏死因子-α诱导的细胞凋亡，而miR-34a-5p模拟物则抑制CTRP6诱导的细胞凋亡。CTRP6可增加唾液细胞AMP活化蛋白激酶(AMPK)的磷酸化，逆转肿瘤坏死因子α诱导的唾液细胞SIRT1下调。AMPK抑制剂AraA逆转了CTRP6对肿瘤坏死因子-α诱导的SIRT1、miR-34a-5p、bc l-2表达的影响，并切割了caspase 3，而AICAR激活AMPK则逆转了肿瘤坏死因子-α诱导的SIRT1表达减少和miR-34a-5p表达增加的作用。EX527抑制SIRT1可抑制CTRP6对肿瘤坏死因子-α诱导的miR-34a-5p和凋亡相关蛋白变化的影响。我们的发现表明，唾液腺是合成和分泌CTRP6的新部位。CTRP6通过AMPK/SIRT1调节miR-34a-5p的表达，保护腺泡细胞免受肿瘤坏死因子-α诱导的细胞凋亡。
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)-alpha 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-alpha, which was abolished by CTRP6. The miR-34a-5p inhibitor promoted whereas the miR-34a-5p mimic suppressed the effects of CTRP6 on TNF-alpha-induced apoptosis. CTRP6 increased AMP-activated protein kinase (AMPK) phosphorylation and reversed TNF-alpha-induced SIRT1 downregulation in salivary cells. AraA, an AMPK inhibitor, reversed the effects of CTRP6 on TNF-alpha-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-alpha. Inhibition of SIRT1 by EX527 suppressed the effects of CTRP6 on TNF-alpha-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-alpha-induced apoptosis via AMPK/SIRT1-modulated miR-34a-5p expression.