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Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury
Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP‐binding cassette (ABC) transpor...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154369/ https://www.ncbi.nlm.nih.gov/pubmed/36271611 http://dx.doi.org/10.1111/bpa.13126 |
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author | Xu, Heng Zheng, Le‐xin Chen, Xue‐Shi Pang, Qiu‐yu Yan, Ya‐nan Liu, Rong Guo, Han‐mu Ren, Zhi‐yang Yang, Yan Gu, Zhi‐ya Gao, Cheng Gao, Yuan Luo, Cheng‐liang Zhao, Ying Wang, Ying Wang, Tao Tao, Lu‐yang |
author_facet | Xu, Heng Zheng, Le‐xin Chen, Xue‐Shi Pang, Qiu‐yu Yan, Ya‐nan Liu, Rong Guo, Han‐mu Ren, Zhi‐yang Yang, Yan Gu, Zhi‐ya Gao, Cheng Gao, Yuan Luo, Cheng‐liang Zhao, Ying Wang, Ying Wang, Tao Tao, Lu‐yang |
author_sort | Xu, Heng |
collection | PubMed |
description | Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP‐binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time‐course changes of cholesterol metabolism‐related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post‐TBI, we generated nestin‐specific Abcg1 knockout (Abcg1‐KO) mice using the Cre/loxP recombination system. These Abcg1‐KO mice showed reduced plasma high‐density lipoprotein cholesterol levels and increased plasma lower‐density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1‐KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1‐KO exacerbated TBI‐induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1‐KO mice partly rescued TBI‐induced neuronal damages mentioned above and improved functional deficits versus vehicle‐treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI. |
format | Online Article Text |
id | pubmed-10154369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101543692023-05-04 Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury Xu, Heng Zheng, Le‐xin Chen, Xue‐Shi Pang, Qiu‐yu Yan, Ya‐nan Liu, Rong Guo, Han‐mu Ren, Zhi‐yang Yang, Yan Gu, Zhi‐ya Gao, Cheng Gao, Yuan Luo, Cheng‐liang Zhao, Ying Wang, Ying Wang, Tao Tao, Lu‐yang Brain Pathol Research Articles Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP‐binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time‐course changes of cholesterol metabolism‐related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post‐TBI, we generated nestin‐specific Abcg1 knockout (Abcg1‐KO) mice using the Cre/loxP recombination system. These Abcg1‐KO mice showed reduced plasma high‐density lipoprotein cholesterol levels and increased plasma lower‐density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1‐KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1‐KO exacerbated TBI‐induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1‐KO mice partly rescued TBI‐induced neuronal damages mentioned above and improved functional deficits versus vehicle‐treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI. John Wiley and Sons Inc. 2022-10-21 /pmc/articles/PMC10154369/ /pubmed/36271611 http://dx.doi.org/10.1111/bpa.13126 Text en © 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Articles Xu, Heng Zheng, Le‐xin Chen, Xue‐Shi Pang, Qiu‐yu Yan, Ya‐nan Liu, Rong Guo, Han‐mu Ren, Zhi‐yang Yang, Yan Gu, Zhi‐ya Gao, Cheng Gao, Yuan Luo, Cheng‐liang Zhao, Ying Wang, Ying Wang, Tao Tao, Lu‐yang Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title | Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title_full | Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title_fullStr | Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title_full_unstemmed | Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title_short | Brain‐specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
title_sort | brain‐specific loss of abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154369/ https://www.ncbi.nlm.nih.gov/pubmed/36271611 http://dx.doi.org/10.1111/bpa.13126 |
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