FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes
FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes
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FTO通过激活JAK2/STAT3通路，降低脂肪细胞m6A水平，抑制uprmt诱导的细胞凋亡
DOI：
10.1007/s10495-021-01683-z
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发表时间：
2021-07-01
期刊：
影响因子：
7.2
通讯作者：
Sun, Chao
中科院分区：
文献类型：
--
作者：
Shen, Zhentong;Liu, Ping;Sun, Chao
脂肪和肥胖相关基因（FTO）作为一种核酸脱甲基酶，在调节脂肪代谢中起着重要作用。然而，FTO如何影响脂肪细胞的凋亡仍然是未知的。在本研究中，我们发现过表达FTO在体内和体外抑制促凋亡因子Caspase-3、Caspase-9和Bax以及线粒体未折叠蛋白反应（UPRmt）标记物HSP 60和ClpP的表达。特别地，FTO的过表达抑制脂肪细胞中的细胞凋亡。进一步的研究表明，FTO通过减少HSP 60 mRNA N6-甲基腺苷（m6 A）修饰来抑制UPRmt。FTO通过JAK 2/STAT 3信号通路抑制脂肪细胞Caspase-3的活化。进一步的实验表明，在脂肪细胞中，促凋亡基因Bax被UPRmt激活的PKR/eIF 2 α/ATF 5轴上调。综上所述，本研究证实了FTO通过激活JAK 2/STAT 3信号通路和抑制UPRmt来减少脂肪细胞凋亡，揭示了FTO诱导脂肪细胞凋亡的新机制，为肥胖及相关代谢综合征的治疗提供了新的潜在疗法。
As a nucleic acid demethylase, Fat and obesity associated gene (FTO) plays a vital role in modulating adipose metabolism. However, it is still unknown how FTO affects apoptosis in adipocytes. In this study, we found that overexpression of FTO inhibited the expression of pro-apoptosis factors Caspase-3, Caspase-9 and Bax and mitochondrial unfolded protein response (UPRmt) markers HSP60 and ClpP in vivo and in vitro. Particularly, overexpression of FTO inhibited mitochondria-dependent apoptosis in adipocytes. Further studies revealed that FTO suppressed UPRmt by reducing HSP60 mRNA N6-methyladenosine (m6A) modification. Moreover, FTO inhibited the activation of Caspase-3 via JAK2/STAT3 signaling pathway in adipocytes. Further experiments showed that pro-apoptosis gene Bax was upregulated by UPRmt-activated PKR/eIF2 alpha/ATF5 axis in adipocytes. In summary, this study confirms that FTO reduces adipocytes apoptosis by activiting JAK2/STAT3 signaling pathway and inhibiting UPRmt, revealing a novel mechanism of FTO on adipocytes apoptosis, which provides some new potential therapy for treating obesity and related metabolic syndromes.