Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs are metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, has been shown to improve glucose homeostasis, blood pressure, and CV health in insulin-resistant or diabetic animals and proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to metabolic and CV health, little is known about mechanisms by which sEH is regulated in vivo. Our recent study demonstrated that in vivo sEH activity, assessed from plasma oxylipin levels, profoundly (3-fold) decreased after a meal in rats. Interestingly, this effect was completely abolished in rats with gut bacteria depleted by antibiotic treatment, suggesting that a gut-bacteria-derived factor(s) may be responsible for the postprandial effect. Gut bacteria produce short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, from nutrients, and plasma SCFA levels rise during feeding. In the present study, we tested the possibility that SCFAs may be involved in the postprandial inhibition of sEH activity. For this, we examined the effects of SCFAs on sEH activity in vitro by measuring EET conversion to diol in liver homogenates. Acetate showed a profound effect to inhibit sEH activity (up to 91%) with EC50 of 39 ± 3 µM (n = 4). In contrast, propionate and butyrate had no significant effects (n = 4 and 5, respectively). The acetate effect occurred at physiological concentrations, suggesting acetate may be an endogenous inhibitor of sEH, and the postprandial inhibition of sEH activity may be mediated by acetate produced by gut bacteria after a meal. Because acetate is produced in vivo predominantly by gut bacteria, these data may explain why the postprandial effect to inhibit sEH was absent in gut-bacteria-depleted rats. Taken together, our data suggest sEH activity may be regulated in vivo by gut bacteria through the production of acetate.
J. Youn: None. Y. Oh: None.
American Diabetes Association (1-16-IBS-332 to J.Y.)