Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
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
_version_ 1785036112457105408
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
work_keys_str_mv AT xuheng brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT zhenglexin brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT chenxueshi brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT pangqiuyu brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT yanyanan brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT liurong brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT guohanmu brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT renzhiyang brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT yangyan brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT guzhiya brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT gaocheng brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT gaoyuan brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT luochengliang brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT zhaoying brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT wangying brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT wangtao brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury
AT taoluyang brainspecificlossofabcg1disturbscholesterolmetabolismandaggravatespyroptosisandneurologicaldeficitsaftertraumaticbraininjury