Endocrine Abstracts

Metabolic-associated fatty liver disease (MAFLD) is a metabolic disorder characterized by excessive lipid accumulation and is associated with irreversible liver cirrhosis and liver cancer. Epoxyeicosatrienoic acids (EETs), which are synthesized from fatty acid metabolism, function primarily as a regulator of vascular tone, anti-inflammation, and angiogenesis. Soluble epoxide hydrolase (sEH) is a key enzyme that converts EET to the less biologically active dihydroxyeicosatrienoic acid (DHET). Thus, the inhibition of sEH is a potential approach to prolong beneficial effects of EETs, and even attenuates high-fat diet (HFD)-induced obesity. However, the regulatory mechanism controlling its effect on hepatic lipid metabolism remains unclear. In present study, sEH knockout (KO) mice and wild type (WT) mice fed with either HFD or chow diet for 16 weeks were used to test our hypothesis. Our results showed that sEH KO mice exhibited lower body weight and liver weight compared with WT mice. Deficiency of sEH significantly reduced HFD-induced hypertriglyceridemia and increased hepatic lipid accumulation compared with the WT group. Meanwhile, results of western blotting showed that deficiency of sEH can activate AMPK signaling, which is a key regulator of cellular energy homeostasis. This activation results in reduced lipid accumulation in hepatocytes. To explore the underlying mechanisms, model of AML12 hepatocytes co-incubated with oleic acid to induce intracellular lipid accumulation were used. Treatment of TPPU, an inhibitor of sEH, caused a dose-dependent reduction in intracellular lipid droplets through AMPK signaling pathway in AML12 hepatocytes. TPPU also downregulated expressions of genes and proteins associated with de novo lipogenesis in AML12 hepatocytes. In conclusion, our study demonstrated that deficiency of sEH activated AMPK-mediated suppression on de novo lipogenesis in liver and ameliorated fatty liver.