Soluble epoxide hydrolase deficiency promotes liver regeneration and ameliorates liver injury in mice by regulating angiocrine factors and angiogenesis

Background: Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear.

Methods: This study used sEH-deficient (sEH^-/-) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for α-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting.

Results: sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH^-/- mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH^-/- mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH^-/- compared to WT mice. Furthermore, sEH deficiency attenuated CCl₄-induced acute liver injury and reduced fibrosis in both CCl₄ and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH^-/- mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH^-/- BDL mice had more Ki67-positive cells in the liver than WT BDL mice.

Conclusions: sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage.