Arsenic induces hepatic insulin resistance via mtROS-NLRP3 inflammasome pathway

  • J Hazard Mater. 2020 Nov 15;399:123034. doi: 10.1016/j.jhazmat.2020.123034.
Xue Jia  1 ,  Tianming Qiu  2 ,  Xiaofeng Yao  3 ,  Liping Jiang  4 ,  Ningning Wang  5 ,  Sen Wei  6 ,  Ye Tao  7 ,  Pei Pei  8 ,  Zhidong Wang  9 ,  Jingyuan Zhang  10 ,  Yuhan Zhu  11 ,  Guang Yang  12 ,  Xiaofang Liu  13 ,  Shuang Liu  14 ,  Xiance Sun  15
Affiliations
  • 1. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 2. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 3. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 4. Experimental Teaching Center of Public Health, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 5. Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 6. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 7. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 8. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 9. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 10. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 11. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 12. Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 13. Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 14. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
  • 15. Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China; Global Health Research Center, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: [email protected].
PMID: 32544768 DOI: 10.1016/j.jhazmat.2020.123034
Abstract

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.

Keywords
Hepatic IR; Mitophagy; MtROS; NLRP3 inflammasome; NaAsO(2).
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