4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic beta-Cell Death via a JNK/AMPK alpha Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

doi:10.3390/ijms22094379

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23689

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23689

Title:	4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic beta-Cell Death via a JNK/AMPK alpha Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway
Authors:	Huang, CC;Yang, CY;Su, CC;Fang, KM;Yen, CC;Lin, CT;Liu, JM;Lee, KI;Chen, YW;Liu, SH;Huang, CF
Keywords:	4-methyl-2;4-bis(4-hydroxyphenyl)pent-1-ene (MBP);β -cells;apoptosis;ER stress;JNK;AMPK945
Date:	2021
Issue Date:	2022-08-05T09:41:18Z (UTC)
Publisher:	MDPI
Abstract:	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 beta-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic beta-cells and elucidated the cellular mechanism involved in MBP-induced beta-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)alpha. Pretreatment of beta-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 AMPK alpha and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on beta-cells via the interdependent activation of JNK and AMPK alpha, which regulates the downstream apoptotic signaling pathway.
URI:	http://dx.doi.org/10.3390/ijms22094379 https://www.webofscience.com/wos/woscc/full-record/WOS:000650379300001 https://ir.csmu.edu.tw:8080/handle/310902500/23689
Relation:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES ,2021,v22,issue 9
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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