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Inhibition of Soluble Epoxide Hydrolase Ameliorates Hyperhomocysteinemia-Induced Hepatic Steatosis by Enhancing β-oxidation of Fatty Acid in Mice.

Hepatic steatosis is the beginning phase of non-alcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-week-old male mice a chow diet or 2% (wt/wt) high methione diet for 8 weeks to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg/kg/day for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated peroxisome proliferator-activated receptor-α (PPARα), as evidenced by elevated β-oxidation of fatty acids and the expression of PPARα target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPARα activation was further confirmed by a marked increase in PPAR response element luciferase activity, which was reversed by knock down of PPARα. Of note, 11,12-EET ligand-dependently activated PPARα. Thus, increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis.

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