School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
Research Center for Brain Health, Pazhou Lab, Guangzhou 510330, China.
Proc Natl Acad Sci U S A. 2023 Jun 27;120(26):e2301360120. doi: 10.1073/pnas.2301360120. Epub 2023 Jun 20.
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 (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.
创伤性脑损伤（TBI）是全球普遍存在的问题，目前尚无有效的治疗方法。尽管大多数研究都集中在受伤大脑的病理学上，但我们注意到肝脏在 TBI 中起着重要作用。使用两种 TBI 小鼠模型，我们发现肝可溶性环氧化物水解酶（sEH）的酶活性在 TBI 后迅速降低，然后恢复正常水平，而在肾脏、心脏、脾脏或肺中则没有观察到这种变化。有趣的是，肝（编码 sEH）的基因下调可改善 TBI 引起的神经功能缺损并促进神经功能恢复，而肝 sEH 的过表达则加剧了与 TBI 相关的神经损伤。此外，发现肝 sEH 消融可促进 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 后血浆中四种 EET（环氧二十碳三烯酸）异构体（5,6-，8,9-，11,12-和 14,15-EET）的血浆水平呈倒 V 形改变，与肝 sEH 活性呈负相关。然而，肝 sEH 的操纵双向调节 14,15-EET 的血浆水平，14,15-EET 可迅速穿过血脑屏障。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-环氧二十碳五烯酸则阻断了这种作用，表明血浆中 14,15-EET 水平的升高介导了肝 sEH 消融后观察到的神经保护作用。这些结果强调了肝脏在 TBI 中的神经保护作用，并表明靶向肝 EET 信号可能是治疗 TBI 的一种有前途的治疗策略。
