Journal
CELL BIOLOGY AND TOXICOLOGY
Volume 39, Issue 5, Pages 2165-2181Publisher
SPRINGER
DOI: 10.1007/s10565-022-09703-7
Keywords
Arsenic; Insulin resistance; m(6)A methylation; AS3MT; Inflammasome
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The relationship between arsenic and metabolic syndromes such as diabetes and fatty liver disease is not clear. This study found that arsenic enhances METTL14-mediated m(6)A methylation, which affects liver insulin sensitivity. Arsenic also interacts with NLRP3 to activate the inflammasome, exacerbating hepatic insulin resistance.
N6-methyladenosine (m(6)A) 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 m(6)A 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 m(6)A 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 arsenicinduced hepatic IR. Also, AS3MT strengthened the m(6)A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m(6)A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.
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