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<sup>-/-</sup>, 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<sup>-/-</sup> 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<sup>-/-</sup> brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1<sup>-/-</sup> 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.
Authors
- Vera F. Monteiro-Cardoso (ORCID: https://orcid.org/0000-0001-7075-7824)
- Mun Geok Yew
- David Castaño (ORCID: https://orcid.org/0000-0003-2781-3135)
- Dong‐Gyu Jo (ORCID: https://orcid.org/0000-0003-2271-1076)
- L. Palomera (ORCID: https://orcid.org/0000-0002-7608-447X)
- Leonard L.L. Yeo (ORCID: https://orcid.org/0000-0002-4249-0402)
- Benjamin Yong‐Qiang Tan (ORCID: https://orcid.org/0000-0003-1824-9077)
- Vijay K. Sharma (ORCID: https://orcid.org/0000-0002-8976-5696)
- Svend Davanger (ORCID: https://orcid.org/0000-0002-1489-037X)
- Xin Yi Yeo (ORCID: https://orcid.org/0000-0003-1546-4564)
- Sejin Lee (ORCID: https://orcid.org/0000-0002-9634-8313)
- Roshni R. Singaraja (ORCID: https://orcid.org/0000-0002-3418-3867)
- Chester Lee Drum (ORCID: https://orcid.org/0000-0001-6327-4584)
- Michael R. Hayden (ORCID: https://orcid.org/0000-0001-5159-1419)
- Seung Hyun Baek (ORCID: https://orcid.org/0000-0002-4863-5529)
- Krishna Kumar
- Lik Hang Wu (ORCID: https://orcid.org/0000-0002-9642-2552)
- Kai Ping Sem
- Sreedharan Sajikumar (ORCID: https://orcid.org/0000-0002-5761-8982)
- Mark Y. Chan (ORCID: https://orcid.org/0000-0003-0389-7450)
- Mariam Wehbe
- Leroy Sivappiragasam Pakkiri (ORCID: https://orcid.org/0000-0003-2768-0918)
- Han‐Gyu Bae (ORCID: https://orcid.org/0000-0001-7542-552X)
- Elisa A. Liehn (ORCID: https://orcid.org/0000-0002-1253-3272)
- Sangyong Jung
- Matthew P. Parsons
- Sangeetha Shanmugam
Institutions
- Agency for Science, Technology and Research (SG)
- Memorial University of Newfoundland (CA)
- University of British Columbia (CA)
- Carol Davila University of Medicine and Pharmacy (RO)
- National University of Singapore (SG)
- University of Southern Denmark (DK)
- University of Oslo (NO)
- Singapore Institute for Clinical Sciences (SG)
- Institutul National Victor Babes (RO)
- National University Hospital (SG)
- National University Health System (SG)
- Yeungnam University (KR)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Journal of Lipid Research
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1016/j.jlr.2024.100712
- Citations
- 7
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.98
Funders
- Agency for Science, Technology and Research
- National University of Singapore
- National Medical Research Council