Arsenic exposure is related to insulin resistance (IR). However, the underlying mechanism is still uncertain. NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome is a key driving factor of IR. We found that NaAsO2 caused hepatic IR, activated NLRP3 inflammasome, and inhibited glycolysis pathway in vivo. We also found that tricarboxylic acid cycle (TCA cycle) was inhibited, and the content of hepatic lactate was upregulated with the treatment of arsenic. Consistent with these findings, we found that NLRP3 inflammasome and glycolysis were involved in the development of IR in L-02 cells. Besides, inhibiting NLRP3 inflammasome upregulated aerobic glycolysis and inhibited anaerobic glycolysis. Moreover, we demonstrated that NLRP3 inflammasome could bind to pyruvate kinase, liver and RBC (PKLR). Simultaneously, insulin signaling rather than NLRP3 inflammasome activation was altered by overexpressing PKLR. In summary, after treatment with NaAsO2, NLRP3 inflammasome blocked the glycolytic pathway via binding to PKLR, which in turn caused hepatic IR. This study shed new light on the molecular mechanism underlying arsenic-induced IR.
Keywords: Glycolysis; Hepatic insulin resistance; NLRP3 inflammasome; NaAsO(2).
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