Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian, 116044, People's Republic of China.
Department of Nutrition and Food Safety, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian, 116044, People's Republic of China.
Cell Biol Toxicol. 2023 Oct;39(5):2165-2181. doi: 10.1007/s10565-022-09703-7. Epub 2022 Feb 28.
N6-methyladenosine (mA) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced mA modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.
N6-甲基腺苷（m6A）信使 RNA 甲基化是影响肝脏功能和疾病的最广泛的基因调控机制。然而，m6A 甲基化与砷诱导的肝胰岛素抵抗（IR）之间的关系尚不清楚，肝胰岛素抵抗是砷诱导的代谢综合征如 2 型糖尿病（T2D）和非酒精性脂肪肝疾病（NAFLD）的关键起始事件。在这里，我们表明砷处理促进了甲基转移酶样蛋白 14（METTL14）介导的 m6A 甲基化，并且 METTL14 干扰逆转了砷损害的肝胰岛素敏感性。我们之前表明，砷诱导的 NOD 样受体蛋白 3（NLRP3）炎症小体激活导致肝 IR。然而，砷对 NLRP3 转录后修饰作用的调节机制尚不清楚。在这里，我们表明在砷诱导的肝 IR 期间，NLRP3 mRNA 的稳定性通过 METTL14 介导的 m6A 甲基化增强。此外，我们证明了砷代谢过程中的必需酶砷甲基转移酶（AS3MT）与 NLRP3 相互作用以激活炎症小体，从而导致砷诱导的肝 IR。此外，AS3MT 增强了 m6A 甲基酶与 NLRP3 的结合，以稳定 m6A 修饰的 NLRP3。总之，我们表明 AS3MT 诱导的 mA 修饰在砷诱导的肝 IR 期间对 NLRP3 炎症小体激活具有重要调节作用，并且我们确定了 AS3MT 在促进砷中毒方面的新的转录后功能。
