<br>m6A 甲基化介导的 PGC-1α 通过调节砷诱导的肝脏胰岛素抵抗中的 GSTK1 促进铁死亡,Science of the Total Environment

当前位置： X-MOL 学术 › Sci. Total Environ. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

m6A 甲基化介导的 PGC-1α 通过调节砷诱导的肝脏胰岛素抵抗中的 GSTK1 促进铁死亡
Science of the Total Environment ( IF 8.2 ) Pub Date : 2023-09-18 , DOI: 10.1016/j.scitotenv.2023.167202
Jingyuan Zhang ₁ , Jinwei Song ₁ , Shuang Liu ₁ , Yuhan Zhang ₁ , Tianming Qiu ₁ , Liping Jiang ₂ , Jie Bai ₃ , Xiaofeng Yao ₁ , Ningning Wang ₃ , Guang Yang ₃ , Xiance Sun ₄

Affiliation

砷暴露与肝脏胰岛素抵抗（IR）和铁死亡密切相关，其机制尚不清楚。过氧化物酶体增殖物 γ 激活受体共激活因子 1-α （PGC-1α）对葡萄糖代谢以及活性氧（ROS）的产生至关重要。然而，目前尚不清楚 PGC-1α 与铁死亡之间是否存在调节联系。此外，砷诱导肝脏 IR 进展的明确机制仍有待确定。在这里，我们发现亚砷酸钠（NaAsO2）损害的肝脏胰岛素敏感性可以通过抑制铁死亡来逆转。从机制上讲，我们发现 PGC-1α 抑制通过核呼吸因子 1 （NRF1）抑制谷胱甘肽 s-转移酶 kappa 1 （GSTK1）的蛋白表达，从而增加 ROS 积累并促进铁死亡。此外，我们发现 NaAsO2 通过甲基转移酶样 14 （METTL14）和包含 YTH 结构域的家族蛋白 2 （YTHDF2）介导的 PGC-1α mRNA 的 N6-甲基腺苷（m6A）诱导肝脏 IR 和铁死亡。总之，NaAsO2 介导的 PGC-1α 抑制是 m6A 甲基化依赖性的，并通过肝脏 IR 中的 PGC-1α/NRF1/GSTK1 通路诱导铁死亡。这些数据可能有助于了解糖尿病预防和治疗的潜在目标。

"点击查看英文标题和摘要"

m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance

Arsenic exposure has been closely linked to hepatic insulin resistance (IR) and ferroptosis with the mechanism elusive. Peroxisome proliferator γ-activated receptor coactivator 1-α (PGC-1α) is essential for glucose metabolism as well as for the production of reactive oxygen species (ROS). However, it was unclear whether there is a regulatory connection between PGC-1α and ferroptosis. Besides, the definitive mechanism of arsenic-induced hepatic IR progression remains to be determined. Here, we found that hepatic insulin sensitivity impaired by sodium arsenite (NaAsO2) could be reversed by inhibiting ferroptosis. Mechanistically, we found that PGC-1α suppression inhibited the protein expression of glutathione s-transferase kappa 1 (GSTK1) via nuclear respiratory factor 1 (NRF1), thereby increasing ROS accumulation and promoting ferroptosis. Furthermore, we showed that NaAsO2 induced hepatic IR and ferroptosis via methyltransferase-like 14 (METTL14) and YTH domain-containing family protein 2 (YTHDF2)-mediated N6-methyladenosine (m6A) of PGC-1α mRNA. In conclusion, NaAsO2-mediated PGC-1α suppression was m6A methylation-dependent and induced ferroptosis via the PGC-1α/NRF1/GSTK1 pathway in hepatic IR. The data might provide insight into potential targets for diabetes prevention and treatment.

更新日期：2023-09-18

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南