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.