Department of Entomology and Nematology, University of California, Davis, CA, USA.
Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA, USA.
J Nutr Biochem. 2017 Nov;49:8-14. doi: 10.1016/j.jnutbio.2017.07.006. Epub 2017 Jul 21.
Epoxides of free fatty acids (FFAs), especially epoxyeicosatrienoic acids (EETs), are lipid mediators with beneficial effects in metabolic and cardiovascular (CV) health. FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EET levels, improves glucose homeostasis and CV health and is proposed as an effective strategy for the treatment of diabetes and CV diseases. Here, we show evidence that sEH activity is profoundly reduced in postprandial states in rats; plasma levels of 17 sEH products (i.e., FFA diols), detected by targeted oxylipin analysis, all decreased after a meal. In addition, the ratios of sEH product to substrate (sEH P/S ratios), which may reflect sEH activity, decreased ~70% on average 2.5 h after a meal in rats (P<.01). To examine whether this effect was mediated by insulin action, a hyperinsulinemic-euglycemic clamp was performed for 2.5 h, and sEH P/S ratios were assessed before and after the clamp. The clamp resulted in small increases rather than decreases in sEH P/S ratios (P<.05), indicating that insulin cannot account for the postprandial decrease in sEH P/S ratios. Interestingly, in rats treated with antibiotics to deplete gut bacteria, the postprandial effect to decrease sEH P/S ratios was completely abolished, suggesting that a gut bacteria-derived factor(s) may be responsible for the effect. Further studies are warranted to identify such a factor(s) and elucidate the mechanism by which sEH activity (or sEH P/S ratio) is reduced in postprandial states.
游离脂肪酸（FFAs）的环氧化物，特别是环氧化物水解酶（sEH），是具有代谢和心血管（CV）健康益处的脂质介质。FFA 环氧化物很快被可溶性环氧化物水解酶（sEH）代谢为生物活性较低的二醇。抑制 sEH 可增加 EET 水平，改善葡萄糖稳态和 CV 健康，并被提议作为治疗糖尿病和 CV 疾病的有效策略。在这里，我们提供证据表明，大鼠在餐后状态下 sEH 活性显著降低；通过靶向氧代脂素分析检测到的 17 种 sEH 产物（即 FFA 二醇）的血浆水平在餐后均降低。此外，sEH 产物与底物的比值（sEH P/S 比值），可反映 sEH 活性，在大鼠餐后 2.5 小时平均降低约 70%（P<.01）。为了研究这种效应是否是由胰岛素作用介导的，进行了 2.5 小时的高胰岛素-正常血糖钳夹实验，并在钳夹前后评估 sEH P/S 比值。钳夹导致 sEH P/S 比值略有增加而不是减少（P<.05），表明胰岛素不能解释餐后 sEH P/S 比值的降低。有趣的是，在使用抗生素耗尽肠道细菌的大鼠中，餐后降低 sEH P/S 比值的作用完全被消除，这表明肠道细菌衍生的某种因子可能是导致这种作用的原因。需要进一步的研究来鉴定这种因子，并阐明餐后 sEH 活性（或 sEH P/S 比值）降低的机制。
