2. Academic Validation
  3. Ubiquitinated gasdermin D mediates arsenic-induced pyroptosis and hepatic insulin resistance in rat liver

Ubiquitinated gasdermin D mediates arsenic-induced pyroptosis and hepatic insulin resistance in rat liver

  • Food Chem Toxicol. 2022 Feb;160:112771. doi: 10.1016/j.fct.2021.112771.
Yuhan Zhu 1,  Jingyuan Zhang 2,  Xiaofeng Yao 3,  Tianming Qiu 4,  Liping Jiang 5,  Ningning Wang 6,  Yan Shi 7,  Chenbing Wu 8,  Weizhuo Yuan 9,  Guang Yang 10,  Xiaofang Liu 11,  Jie Bai 12,  Lili Men 13,  Xiance Sun 14
Affiliations

Affiliations

  • 1 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 928859535@qq.com.
  • 2 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 13704357701@163.com.
  • 3 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: yaoxiaofeng@dmu.edu.cn.
  • 4 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: qtm1992@163.com.
  • 5 Experimental Teaching Center of Public Health, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 1423563234@qq.com.
  • 6 Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: zkxwnn@dmu.edu.cn.
  • 7 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 1124409894@qq.com.
  • 8 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 978192507@qq.com.
  • 9 Occupational and Environmental Health Department, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: 1161009929@qq.com.
  • 10 Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: yg290@163.com.
  • 11 Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: food@dlmedu.edu.cn.
  • 12 Nutrition and Food Hygiene, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, PR China. Electronic address: woshixiaobaige@163.com.
  • 13 Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China. Electronic address: mll0902@163.com.
  • 14 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: sunxiance@dmu.edu.cn.
PMID: 34920032 DOI: 10.1016/j.fct.2021.112771
Abstract

As an environmental toxicant, arsenic exposure may cause Insulin resistance (IR). Previous studies have shown that Pyroptosis plays an important role in the occurrence and development of IR. Although gasdermin D (GSDMD) functions as an executor of Pyroptosis, the relationship between GSDMD-mediated Pyroptosis and hepatic IR remains unclear. Here, we observed that sodium arsenite (NaAsO2) activated NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasomes, promoted GSDMD activation, induced Pyroptosis and hepatic IR, while GSDMD knockdown attenuated Pyroptosis and hepatic IR caused by NaAsO2. However, GSDMD interference did not affect NLRP3 activation. Ubiquitination modification is widely involved in protein regulation and intracellular signal transduction, and whether it regulates GSDMD and affects its degradation, and exerts effects on arsenic-induced Pyroptosis remain unclear. We observed that NaAsO2 reduced the K48- and K63-linked ubiquitination of GSDMD, thereby inhibiting its degradation through the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), causing GSDMD to accumulate and lyse into GSDMD-N, which promoted Pyroptosis. In summary, we demonstrated that GSDMD participated in arsenic-induced hepatic IR. Moreover, NaAsO2 reduced GSDMD ubiquitination and decreased its intracellular degradation, aggravating Pyroptosis and hepatic IR. We have revealed the molecular mechanism underpinning arsenic-induced IR, and we provide potential solutions for the prevention and treatment of type 2 diabetes (T2D).

Keywords

Gasdermin D; Insulin resistance; Pyroptosis; Sodium arsenite; Ubiquitination.

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