Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner
Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner
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DOI：
10.1096/fj.202000830r
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发表时间：
2020-06-24
期刊：
影响因子：
4.8
通讯作者：
Shaikh, Saame Raza
中科院分区：
文献类型：
--
作者：
Pal, Anandita;Al-Shaer, Abrar E.;Shaikh, Saame Raza
二十碳五烯酸（EPA）在REDUCE-IT试验成功后引起了人们的关注，该试验与之前关于EPA对心血管疾病风险的结论相矛盾。在这里，我们首先研究了EPA对高血糖和高胰岛素血症的预防作用。EPA乙酯可预防C57 BL/6 J小鼠肥胖诱导的葡萄糖耐受不良、高胰岛素血症和高血糖症。支持NHANES分析表明，肥胖成年人的空腹血糖水平与EPA摄入量呈负相关。我们接下来研究了EPA如何改善小鼠高胰岛素血症和高血糖症。EPA推翻了肥胖导致的白色脂肪组织和肝脏中18-羟基二十碳五烯酸（18-HEPE）浓度下降。用RvE 1（18-HEPE的下游免疫溶解代谢物，而不是18-HEPE本身）治疗肥胖近交系小鼠，通过G蛋白偶联受体ERV 1/ChemR 23逆转高胰岛素血症和高血糖症。为了解释这些发现，我们确定了RvE 1的影响是否依赖于宿主遗传学。RvE 1对高胰岛素血症和高血糖症的影响在模拟人类遗传变异的多种远交小鼠中是不同的。二级SNP分析进一步证实了人类RvE 1/EPA代谢基因的广泛遗传变异。总的来说，数据表明EPA预防高胰岛素血症和高血糖症，部分是通过RvE 1以宿主遗传方式激活ERV 1/ChemR 23。这些研究强调了基于遗传/代谢酶谱的RvE 1个性化给药的必要性。
Eicosapentaenoic acid (EPA) has garnered attention after the success of the REDUCE-IT trial, which contradicted previous conclusions on EPA for cardiovascular disease risk. Here we first investigated EPA's preventative role on hyperglycemia and hyperinsulinemia. EPA ethyl esters prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia in C57BL/6J mice. Supporting NHANES analyses showed that fasting glucose levels of obese adults were inversely related to EPA intake. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese inbred mice with RvE1, the downstream immunoresolvant metabolite of 18-HEPE, but not 18-HEPE itself, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. To translate the findings, we determined if the effects of RvE1 were dependent on host genetics. RvE1's effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further confirmed extensive genetic variation in human RvE1/EPA-metabolizing genes. Collectively, the data suggest EPA prevents hyperinsulinemia and hyperglycemia, in part, through RvE1's activation of ERV1/ChemR23 in a host genetic manner. The studies underscore the need for personalized administration of RvE1 based on genetic/metabolic enzyme profiles.