Journal
CELL REPORTS
Volume 29, Issue 10, Pages 3223-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.006
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Funding
- National Natural Science Foundation of China [81930034, 81325008]
- Natural Science Foundation of Guangdong Province [2016A030308005]
- Guangzhou Science and Technology Plan Project [201804020061]
- Science and Technology Program of Guangdong [2018B030334001]
- China Postdoctoral Science Foundation [2015M582395]
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Major 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.
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