The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice

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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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-01-01
Series:Journal of Lipid Research
Subjects:
bile acids
excitotoxicity
stroke
chenodeoxycholic acid
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227524002177
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Summary: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.
ISSN:0022-2275

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