Arsenic induces hepatic insulin resistance via mtROS-NLRP3 inflammasome pathway

Hepatic insulin resistance (IR) is the key event for arsenic-caused type 2 diabetes (T2D). However, the unequivocal mechanism of arsenic-induced hepatic IR remains unclear. The current study determined the role of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in arsenic-induced IR and revealed the underlying mechanism. Three-month NaAsO₂ gavage led to glucose intolerance and insulin insensitivity, impaired hepatic insulin signaling. Additionally, NaAsO₂ upregulated the level of oxidized mitochondrial DNA (ox-mtDNA) and mitophagy, thereby activating the NLRP3 inflammasome in SD rat liver. In vitro, we demonstrated that NaAsO₂-induced IR depended upon the NLRP3 inflammasome activation. Moreover, inhibiting mitophagy mitigated the NLRP3 inflammasome activation and impaired insulin signaling induced by NaAsO₂. Furthermore, mitochondrial reactive oxygen species (mtROS) scavenger alleviated the upregulated ox-mtDNA and mitophagy, thereby inhibiting the NLRP3 inflammasome activation, and improving insulin signaling. Taken together, these data demonstrated that mtROS-triggered ox-mtDNA, mitophagy, and the activation of NLRP3 inflammasome was involved in arsenic-induced hepatic IR.