Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
EBioMedicine. 2018 Jan;27:200-213. doi: 10.1016/j.ebiom.2017.12.019. Epub 2017 Dec 19.
Prescription ω-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ω-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ω-3 fatty acid prescriptions.
处方ω-3 脂肪酸乙酯补充剂通常用于治疗高甘油三酯血症。然而，这些治疗方法形成的代谢物的代谢谱和作用仍不清楚。在这里，我们利用无偏代谢组学方法鉴定出 3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）是人类Lovaza™处方ω-3 酸乙酯的一种重要代谢物。在高脂肪饮食喂养前后，以与人类观察到的暴露量相当的剂量给予 CMPF 处理，可增加全身脂质代谢，改善胰岛素敏感性，增加β氧化，减少脂肪生成基因表达，并改善脂肪变性。从机制上讲，我们发现 CMPF 可急性抑制 ACC 活性，并诱导 SREBP1c 和 ACC1/2 表达的长期丧失。这对应于 FGF21 的诱导，这对于长期脂肪变性保护是必需的，因为 FGF21KO 小鼠对改善的代谢作用没有反应。因此，CMPF 在小鼠中的处理与人类Lovaza™补充的作用相似，表明 CMPF 可能有助于解释观察到的 ω-3 脂肪酸处方的改善代谢作用。
Zotero 插件
