Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress

Publication date: 3 December 2019Source: Cell Reports, Volume 29, Issue 10Author(s): Xi-He Qin, Zhou Wu, Jing-Hua Dong, Yuan-Ning Zeng, Wen-Chao Xiong, Ce Liu, Meng-Yao Wang, Min-Zhen Zhu, Wen-Jun Chen, Yuan Zhang, Qi-Yuan Huang, Xin-Hong ZhuSummaryMajor depression is a serious global health concern; however, the pathophysiology underlying this condition remains unclear. While numerous studies have focused on brain-specific mechanisms, few have evaluated the role of peripheral organs in depression. Here, we show that the liver activates an intrinsic metabolic pathway that can modulate depressive-like behavior. We find that chronic stress specifically increases the protein levels of monomeric and oligomeric soluble epoxide hydrolase (sEH), a key enzyme in epoxyeicosatrienoic acid (EET) signaling, in the liver. Hepatic deletion of Ephx2 (which encodes sEH) results in antidepressant-like effects, while the hepatic overexpression of sEH induces depressive phenotypes. The activity of sEH in hepatocytes modulates the plasma levels of 14,15-EET, which then interacts with astrocytes in the medial prefrontal cortex to mediate the effects of hepatic Ephx2 deletion. These results suggest that targeting mechanisms underlying the hepatic response to stress would increase our therapeutic options for the treatment of depression.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research