https://scholars.lib.ntu.edu.tw/handle/123456789/566115
標題: | 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway | 作者: | Huang, Cheng-Chin CHING-YAO YANG Su, Chin-Chuan Fang, Kai-Min Yen, Cheng-Chieh Lin, Ching-Ting Liu, Jui-Min Lee, Kuan-I Chen, Ya-Wen SHING-HWA LIU Huang, Chun-Fa |
關鍵字: | 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP); AMPKα; ER stress; JNK; apoptosis; β-cells | 公開日期: | 22-四月-2021 | 卷: | 22 | 期: | 9 | 來源出版物: | International journal of molecular sciences | 摘要: | 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/566115 | ISSN: | 16616596 | DOI: | 10.3390/ijms22094379 |
顯示於: | 醫學系 |
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