Journal article
Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells to arsenite-induced cytotoxicity
Toxicology and applied pharmacology, Vol.329, pp.67-74
08/15/2017
DOI: 10.1016/j.taap.2017.05.013
PMID: 28549828
Abstract
Increasing evidence indicates that chronic inorganic arsenic exposure is associated with type 2 diabetes (T2D), a disease of growing prevalence. Pancreatic β-cells were targeted and damaged by oxidative stress induced by arsenite. We previously showed that nuclear factor erythroid 2 like 2 (Nfe2l2)-deficient pancreatic β-cells were vulnerable to cell damage induced by oxidative stressors including arsenite, due to a muted antioxidant response. Like nuclear factor erythroid 2 like 2 (NFE2L2), NFE2L1 also belongs to the cap ‘n’ collar (CNC) basic-region leucine zipper (bZIP) transcription factor family, and regulates antioxidant response element (ARE) related genes. Our prior work showed NFE2L1 regulates glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated islets. In the current study, we demonstrated that MIN6 cells with a specific knockdown of long isoforms of Nfe2l1 (L-Nfe2l1) by lentiviral shRNA (Nfe2l1(L)-KD) were vulnerable to arsenite-induced apoptosis and cell damage. The expression levels of antioxidant genes, such as Gclc, Gclm and Ho-1, and intracellular reactive oxygen species (ROS) levels were not different in Scramble and Nfe2l1(L)-KD cells, while the expression of arsenic metabolism related-genes, such as Gsto1, Gstm1 and Nqo1, increased in Nfe2l1(L)-KD cells with or without arsenite treatment. The up-regulation of arsenic biotransformation genes was due to activated NFE2L2 in Nfe2l1(L)-KD MIN6 cells. Furthermore, the level of intracellular monomethylarsenic (MMA) was higher in Nfe2l1(L)-KD MIN6 cells than in Scramble cells. These results showed that deficiency of L-Nfe2l1 in pancreatic β-cells increased susceptibility to acute arsenite-induced cytotoxicity by promoting arsenic biotransformation and intracellular MMA levels.
•Nfe2l1(L)-KD MIN6 cells are vulnerable to arsenite-induced cell damage.•Deficiency of L-Nfe2l1 activates NFE2L2 in MIN6 pancreatic β-cells.•Arsenic metabolism related-genes are up-regulated in Nfe2l1(L)-KD MIN6 cells.•L-Nfe2l1 is involved in the regulation of arsenic biotransformation in M.
Details
- Title: Subtitle
- Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells to arsenite-induced cytotoxicity
- Creators
- Qi Cui - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Jingqi Fu - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Yuxin Hu - China Medical UniversityYongfang Li - China Medical UniversityBei Yang - Department of Histology and Embryology, School of Basic Medical Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China.Lu Li - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Jing Sun - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Chengjie Chen - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Guifan Sun - China Medical UniversityYuanyuan Xu - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Qiang Zhang - Emory UniversityJingbo Pi - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.329, pp.67-74
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.taap.2017.05.013
- PMID
- 28549828
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81402635, 81573106, 81602825; DOI: 10.13039/501100007300, name: China Medical University; name: Liaoning Pandeng Scholar Program; name: Program for Liaoning Innovative Research Team, award: LT2015028
- Language
- English
- Date published
- 08/15/2017
- Academic Unit
- Neurology
- Record Identifier
- 9984302213602771
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