Inhibition of Soluble Epoxide Hydrolase Attenuates High-Fat-Diet–Induced Hepatic Steatosis by Reduced Systemic Inflammatory Status in Mice

Abstract

Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet–induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH-null mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet–increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet–induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet–induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet–induced hepatic steatosis in inhibiting systemic inflammation.

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

“…The inhibitory activity of the congeners with a phenylamine derivative as the N-linked side chain (such as SMTP-26, SMTP-27, and SMTP-28) (12) were potent with respect to both the Cterm-EH and Nterm-phos inhibitions. The variability of the inhibition selectivity (IC 50 for the Cterm-EH versus that for the Ntermphos) supports the idea that SMTPs bind to two distinct sites in sEH.…”

“…3, A and B). In addition, the structurally simplest congener SMTP-0 (which lacks the N-linked side chain) was inhibitory to both activities (IC 50 6 Ϯ 1 and 14 Ϯ 1 M, respectively) (Fig. 3, A and B).…”

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

“…The liver and kidney tissues were homogenized in deionized water with 1 mM PMSF, and cytosolic supernatants were obtained by centrifugation at 3,500 x g for 10 min at 4˚C. The activity of sEH in the hepatic and renal homogenates was determined using Epoxy fluor 7 (Cayman Chemical Company, Ann Arbor, MI, USA) and the sEH inhibitor, trans-4-[4-(3-adamantan-1-ylureido)-cyclohex yloxy]-benzoic acid (t-AUCB), as previously described (14). The sEH inhibitor, t-AUCB, was obtained from Professor Bruce D. Hammock (Department of Entomology and UCD Cancer Research Center, University of California, Davis, CA, USA).…”

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

“…The sEHI t-AUCB alleviated diet-induced characteristics of metabolic diseases, including glucose, insulin, and lipid abnormalities, as well as pancreatic and liver structural changes (30). sEH deficiency or inhibition also attenuated diet-induced endoplasmic reticulum stress in liver and adipose tissue (18).…”

“…Recent data suggest that CYP epoxygenases and EETs are involved in the homeostasis of metabolic diseases, including obesity and diabetes (15,16). Previous studies have also shown that sEH is expressed in adipose tissue (17)(18)(19), hepatocytes (17,18), and pancreatic islets (2,(19)(20)(21). At least in part, it is speculated that EETs play an important role in the treatment of diet-associated metabolic diseases.…”