Impairment of endoplasmic reticulum is involved in β-cell dysfunction induced by microcystin-LR.
Microcystins (MCs) widely distributed in freshwaters have posed a significant risk to human health. Previous studies have demonstrated that exposure to MC-LR impairs pancreatic islet function, however, the underlying mechanisms still remain unclear. In the present study, we explored the role of endoplasmic reticulum (ER) impairment in β-cell dysfunction caused by MC-LR. The result showed that MC-LR modified ER morphology evidenced by increased ER amount and size at low doses (15, 30 or 60 μM) and vacuolar and dilated ER ultrastructure at high doses (100 or 200 μM). Also, insulin content showed increased at 15 or 30 μM but declined at 60, 100, or 200 μM, which was highly accordant with ER morphological alteration. Transcriptomic analysis identified a number of factors and several pathways associated with ER protein processing, ER stress, apoptosis, and diabetes mellitus in the cells treated with MC-LR compared with non-treated cells. Furthermore, MC-LR-induced ER stress significantly promoted the expression of PERK/eIF2α and their downstream targets (ATF4, CHOP, and Gadd34), which indicates that PERK-eIF2α-ATF4 pathway is involved in MC-LR-induced insulin deficiency. These results suggest that ER impairment is an important contributor to MC-LR-caused β-cell failure and provide a new insight into the association between MCs contamination and the occurrence of human diseases.
State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China.
Yanyan
Y
Zhao
State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China.
Qing
Q
Cao
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China.
Yaojia
Y
He
State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China.
Qingju
Q
Xue
State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China. Electronic address: liqxie@gmail.com.
Liqiang
L
Xie
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China. Electronic address: yanyunjun@hust.edu.cn.
Yunjun
Y
Yan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D051381:Rats; D014874:Water Pollutants, Chemical / Q000633:toxicity
D001427:Bacterial Toxins; D007328:Insulin; D008387:Marine Toxins; D052998:Microcystins; D014874:Water Pollutants, Chemical; C057862:cyanoginosin LR
Cyanobacteria; Endoplasmic reticulum stress; Microcystin-LR; Transcriptomics; β-Cell failure