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
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/9/4379 |
| _version_ | 1797536718638809088 |
|---|---|
| author | Cheng-Chin Huang Ching-Yao Yang Chin-Chuan Su Kai-Min Fang Cheng-Chieh Yen Ching-Ting Lin Jui-Min Liu Kuan-I Lee Ya-Wen Chen Shing-Hwa Liu Chun-Fa Huang |
| author_facet | Cheng-Chin Huang Ching-Yao Yang Chin-Chuan Su Kai-Min Fang Cheng-Chieh Yen Ching-Ting Lin Jui-Min Liu Kuan-I Lee Ya-Wen Chen Shing-Hwa Liu Chun-Fa Huang |
| author_sort | Cheng-Chin Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:04:47Z |
| format | Article |
| id | doaj.art-7c4acce57408493cb2e998e79e45bada |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:04:47Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7c4acce57408493cb2e998e79e45bada2023-11-21T16:41:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01229437910.3390/ijms220943794-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 PathwayCheng-Chin Huang0Ching-Yao Yang1Chin-Chuan Su2Kai-Min Fang3Cheng-Chieh Yen4Ching-Ting Lin5Jui-Min Liu6Kuan-I Lee7Ya-Wen Chen8Shing-Hwa Liu9Chun-Fa Huang10Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, TaiwanDepartment of Surgery, National Taiwan University Hospital, Taipei 100, TaiwanDepartment of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, TaiwanDepartment of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, TaiwanDepartment of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung 402, TaiwanSchool of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, TaiwanDepartment of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, TaiwanDepartment of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, TaiwanDepartment of Physiology and Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung 404, TaiwanInstitute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, TaiwanSchool of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan4-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.https://www.mdpi.com/1422-0067/22/9/43794-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP)β-cellsapoptosisER stressJNKAMPKα |
| spellingShingle | Cheng-Chin Huang Ching-Yao Yang Chin-Chuan Su Kai-Min Fang Cheng-Chieh Yen Ching-Ting Lin Jui-Min Liu Kuan-I Lee Ya-Wen Chen Shing-Hwa Liu Chun-Fa Huang 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 International Journal of Molecular Sciences 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) β-cells apoptosis ER stress JNK AMPKα |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) β-cells apoptosis ER stress JNK AMPKα |
| url | https://www.mdpi.com/1422-0067/22/9/4379 |
| work_keys_str_mv | AT chengchinhuang 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT chingyaoyang 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT chinchuansu 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT kaiminfang 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT chengchiehyen 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT chingtinglin 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT juiminliu 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT kuanilee 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT yawenchen 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT shinghwaliu 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway AT chunfahuang 4methyl24bis4hydroxyphenylpent1eneamajoractivemetaboliteofbisphenolatriggerspancreaticbcelldeathviaajnkampkaactivationregulatedendoplasmicreticulumstressmediatedapoptoticpathway |