The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice
Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1−/−, and in Wt mice administ...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002177 |
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| author | Vera F. Monteiro-Cardoso Xin Yi Yeo Han-Gyu Bae David Castano Mayan Mariam Wehbe Sejin Lee Kumar Krishna-K Seung Hyun Baek Leon F. Palomera Lik Hang Wu Leroy S. Pakkiri Sangeetha Shanmugam Kai Ping Sem Mun Geok Yew Matthew P. Parsons Michael R. Hayden Leonard L.L. Yeo Vijay K. Sharma Chester Drum Elisa A. Liehn Sreedharan Sajikumar Svend Davanger Dong-Gyu Jo Mark Y.Y. Chan Benjamin Y.Q. Tan Sangyong Jung Roshni R. Singaraja |
| author_facet | Vera F. Monteiro-Cardoso Xin Yi Yeo Han-Gyu Bae David Castano Mayan Mariam Wehbe Sejin Lee Kumar Krishna-K Seung Hyun Baek Leon F. Palomera Lik Hang Wu Leroy S. Pakkiri Sangeetha Shanmugam Kai Ping Sem Mun Geok Yew Matthew P. Parsons Michael R. Hayden Leonard L.L. Yeo Vijay K. Sharma Chester Drum Elisa A. Liehn Sreedharan Sajikumar Svend Davanger Dong-Gyu Jo Mark Y.Y. Chan Benjamin Y.Q. Tan Sangyong Jung Roshni R. Singaraja |
| author_sort | Vera F. Monteiro-Cardoso |
| collection | DOAJ |
| description | Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1−/−, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1−/− and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1−/− brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1−/− mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke. |
| format | Article |
| id | doaj-art-df682c2301f24932a00551c39b2f396f |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-df682c2301f24932a00551c39b2f396f2025-01-30T05:12:38ZengElsevierJournal of Lipid Research0022-22752025-01-01661100712The bile acid chenodeoxycholic acid associates with reduced stroke in humans and miceVera F. Monteiro-Cardoso0Xin Yi Yeo1Han-Gyu Bae2David Castano Mayan3Mariam Wehbe4Sejin Lee5Kumar Krishna-K6Seung Hyun Baek7Leon F. Palomera8Lik Hang Wu9Leroy S. Pakkiri10Sangeetha Shanmugam11Kai Ping Sem12Mun Geok Yew13Matthew P. Parsons14Michael R. Hayden15Leonard L.L. Yeo16Vijay K. Sharma17Chester Drum18Elisa A. Liehn19Sreedharan Sajikumar20Svend Davanger21Dong-Gyu Jo22Mark Y.Y. Chan23Benjamin Y.Q. Tan24Sangyong Jung25Roshni R. Singaraja26Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, SingaporeInstitute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Medical Science, College of Medicine, CHA University, Pocheon, Republic of KoreaInstitute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Life Sciences, Yeungnam University, Gyeongsan, South KoreaYong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Cardiovascular Research Institute, National University Health System, Singapore, SingaporeInstitute of Basic Medical Sciences, University of Oslo, Oslo, NorwayInstitute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, SingaporeDepartment of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, SingaporeSchool of Pharmacy, Sungkyunkwan University, Suwon, Republic of KoreaSchool of Pharmacy, Sungkyunkwan University, Suwon, Republic of KoreaYong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeYong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeTranslational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, SingaporeTranslational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, SingaporeYong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDivision of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, CanadaDepartment of Medical Genetics, Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, CanadaYong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, SingaporeYong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, SingaporeYong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeInstitute for Innovation and eHealth, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania; The Heart Center, Singapore, SingaporeDepartment of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, SingaporeInstitute of Basic Medical Sciences, University of Oslo, Oslo, NorwaySchool of Pharmacy, Sungkyunkwan University, Suwon, Republic of KoreaYong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeYong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Neurology, Department of Medicine, National University Hospital, Singapore, SingaporeInstitute for Molecular and Cellular Biology, Agency for Science, Technology and Research, Singapore, Singapore; Department of Medical Science, College of Medicine, CHA University, Pocheon, Republic of Korea; Department of Physiology and Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; For correspondence: Sangyong Jung; Roshni R. SingarajaYong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Cardiovascular Research Institute, National University Health System, Singapore, Singapore; For correspondence: Sangyong Jung; Roshni R. SingarajaBile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1−/−, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1−/− and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1−/− brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1−/− mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.http://www.sciencedirect.com/science/article/pii/S0022227524002177bile acidsexcitotoxicitystrokechenodeoxycholic acid |
| spellingShingle | Vera F. Monteiro-Cardoso Xin Yi Yeo Han-Gyu Bae David Castano Mayan Mariam Wehbe Sejin Lee Kumar Krishna-K Seung Hyun Baek Leon F. Palomera Lik Hang Wu Leroy S. Pakkiri Sangeetha Shanmugam Kai Ping Sem Mun Geok Yew Matthew P. Parsons Michael R. Hayden Leonard L.L. Yeo Vijay K. Sharma Chester Drum Elisa A. Liehn Sreedharan Sajikumar Svend Davanger Dong-Gyu Jo Mark Y.Y. Chan Benjamin Y.Q. Tan Sangyong Jung Roshni R. Singaraja The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice Journal of Lipid Research bile acids excitotoxicity stroke chenodeoxycholic acid |
| title | The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| title_full | The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| title_fullStr | The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| title_full_unstemmed | The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| title_short | The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| title_sort | bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice |
| topic | bile acids excitotoxicity stroke chenodeoxycholic acid |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002177 |
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