Enhancement of the liver's neuroprotective role ameliorates traumatic brain injury pathology.
Enhancement of the liver's neuroprotective role ameliorates traumatic brain injury pathology.
复制标题
增强肝脏的神经保护作用可改善创伤性脑损伤病理学。
DOI：
10.1073/pnas.2301360120
复制
发表时间：
2023-06-27
影响因子：
11.1
通讯作者：
Zhu, Xinhong
中科院分区：
文献类型：
--
作者：
Dai, Yongfeng;Dong, Jinghua;Wu, Yu;Zhu, Minzhen;Xiong, Wenchao;Li, Huanyu;Zhao, Yulu;Hammock, Bruce D.;Zhu, Xinhong
迄今为止，没有有效的治疗方法可用于创伤性脑损伤（TBI）。在这里，我们确定了肝脏在TBI中的神经保护作用。肝sEH（可溶性环氧化物水解酶）活性在TBI后发生特异性改变，并与血浆14，15-EET（-环氧二十碳三烯酸）水平呈负相关。肝脏sEH操作通过调节A2表型星形胶质细胞的产生双向调节TBI诱导的神经功能缺损。外周14，15-EET迅速穿过血脑屏障。此外，14，15-EET模拟了肝脏Ephx 2缺失的神经保护作用，而14，15-环氧二十碳-5（Z）-烯酸则阻断了TBI后肝脏sEH消融的神经保护作用。这些结果突出了肝脏在TBI中的神经保护作用，并表明靶向这种神经保护作用可能代表TBI的有希望的治疗策略。创伤性脑损伤（TBI）是世界范围内普遍存在的问题，目前尚无有效的治疗方法。虽然大多数研究都集中在损伤的大脑的病理学，我们已经注意到，肝脏在TBI中起着重要的作用。使用两个小鼠模型TBI，我们发现，肝可溶性环氧化物水解酶（sEH）的酶活性迅速下降，然后恢复到正常水平TBI后，而这种变化没有观察到在肾脏，心脏，脾脏，或肺。有趣的是，肝Ephx 2（其编码sEH）的遗传下调改善了TBI诱导的神经缺陷并促进神经功能恢复，而肝sEH的过表达加剧了TBI相关的神经损伤。此外，发现肝sEH消融促进A2表型星形胶质细胞的产生，并促进TBI后与星形胶质细胞相关的各种神经保护因子的产生。我们还观察到TBI后4种EET（环氧二十碳三烯酸）亚型（5，6-，8，9-，11，12-和14，15-EET）的血浆水平呈倒V形变化，与肝脏sEH活性呈负相关。然而，肝脏sEH操纵双向调节14，15-EET的血浆水平，其迅速穿过血脑屏障。此外，我们发现14，15-EET的应用模拟了肝sEH消融的神经保护作用，而14，15-环氧二十碳-5（Z）-烯酸阻断了这种作用，表明14，15-EET的血浆水平增加介导了肝sEH消融后观察到的神经保护作用。这些结果突出了肝脏在TBI中的神经保护作用，并表明靶向肝脏EET信号传导可能代表治疗TBI的有希望的治疗策略。
To date, no effective treatments are available for traumatic brain injury (TBI). Here, we identified the neuroprotective role of the liver in TBI. Hepatic sEH (soluble epoxide hydrolase) activity was specifically altered following TBI and negatively correlated with the plasma levels of 14,15-EET (-epoxyeicosatrienoic acid). Hepatic sEH manipulation bidirectionally modulated TBI-induced neurological deficits by regulating the generation of A2 phenotype astrocytes. Peripheral 14,15-EET rapidly crossed the blood–brain barrier. Moreover, 14,15-EET mimicked the neuroprotective effects of hepatic Ephx2 deletion, whereas 14,15-epoxyeicosa-5(Z)-enoic acid blocked the neuroprotective effects of hepatic sEH ablation following TBI. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting this neuroprotective role may represent a promising therapeutic strategy for TBI. Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2 (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 phenotype astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and 14,15-EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15-EET, which rapidly crosses the blood–brain barrier. Additionally, we found that the application of 14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating that the increased plasma levels of 14,15-EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.
登录
查看更多内容
影响因子：
4.2
作者：
Kattenhorn LM;Tipper CH;Stoica L;Geraghty DS;Wright TL;Clark KR;Wadsworth SC
通讯作者：
Wadsworth SC
影响因子：
--
作者：
Alqahtani F;Assiri MA;Mohany M;Imran I;Javaid S;Rasool MF;Shakeel W;Sivandzade F;Alanazi AZ;Al-Rejaie SS;Alshammari MA;Alasmari F;Alanazi MM;Alamri FF
通讯作者：
Alamri FF
影响因子：
15.1
作者：
Ma MW;Wang J;Zhang Q;Wang R;Dhandapani KM;Vadlamudi RK;Brann DW
通讯作者：
Brann DW
影响因子：
14.8
作者：
Flierl, Michael A.;Stahel, Philip F.;Shohami, Esther
通讯作者：
Shohami, Esther
影响因子：
29
作者：
Arnoriaga-Rodriguez, Maria;Mayneris-Perxachs, Jordi;Fernandez-Real, Jose Manuel
通讯作者：
Fernandez-Real, Jose Manuel