Enhancement of the liver’s neuroprotective role ameliorates traumatic brain injury pathology

Abstract

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.

Determinants of Meal-Induced Changes in Circulating FFA Epoxides, Diols, and Diol-to-Epoxide Ratios as Indices of Soluble Epoxide Hydrolase Activity

“…However, based on similar changes not only in D-to-E ratios but also in EpFA and diol levels between plasma and the liver (Figure 2), together with the hepatic capacities to generate EpFAs and diols and exchange metabolites with plasma, as discussed above, we believe the liver may be the tissue driving all these changes. Similar conclusions were recently drawn based on studies with hepatocyte selective sEH knockouts or sEH reduction associated with brain injuries [25,26].…”

“…This intriguing possibility needs to be directly tested in future studies. Hepatic-sEH activity was decreased without changes in sEH proteins during brain injuries [26].…”

Transforming growth factor-β1 protects mechanically injured cortical murine neurons by reducing trauma-induced autophagy and apoptosis

“…Mechanically damaged neurons in TBI patients often experience a loss of biological function, leading to cognitive impairment. It is crucial to identify a medication that can prevent the death of damaged neurons while preserving their normal activity ( Dai et al, 2023 ; Yang et al, 2024 ). TGF-β1, a cytokine involved in regulating various cellular pathways, has shown multiple benefits in TBI treatment by contributing to immune regulation in traumatic brain injuries.…”

Liver Protects Cytoarchitecture, Neuron Viability and Electrocortical Activity in Post-Cardiac Arrest Brain Injury

“…This suggests a possible mechanism through which the liver’s metabolic regulatory functions could contribute to the overall protection of the brain during ischemic insults. Previous studies have demonstrated that hepatic soluble epoxide hydrolase (sEH) activity was specifically altered following traumatic brain injury (TBI) and negatively correlated with the plasma levels of 14,15,-epoxyeicosatrienoic acid, which shows neuroprotective effects in the controlled cortical injury mouse model 30 . Hepatic sEH activity also plays roles in regulating cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice 31 .…”