CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis.
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis.
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DOI：
10.1016/j.ebiom.2017.12.019
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发表时间：
2018-01
期刊：
影响因子：
11.1
通讯作者：
Wheeler MB
中科院分区：
文献类型：
--
作者：
Prentice KJ;Wendell SG;Liu Y;Eversley JA;Salvatore SR;Mohan H;Brandt SL;Adams AC;Serena Wang X;Wei D;FitzGerald GA;Durham TB;Hammond CD;Sloop KW;Skarke C;Schopfer FJ;Wheeler MB
处方ω-3脂肪酸乙酯补充剂常用于治疗高甘油三酯血症。然而，这些治疗形成的代谢特征和代谢物的影响仍然未知。在这里，我们利用无偏代谢组学鉴定了3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）是ω-3-酸乙酯处方Lovaza™在人体中的重要代谢物。在高脂饮食喂养之前或之后给小鼠施用CMPF，其暴露量与在人类中观察到的暴露量相当，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。在机制上，我们发现CMPF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，这是长期脂肪变性保护所必需的，因为FGF21KO小鼠对改善的代谢作用是难以耐受的。因此，小鼠CMPF治疗与人类Lovaza™补充剂的效果相似，表明CMPF可能有助于ω-3脂肪酸处方中观察到的代谢改善效果。CMPF是一种丰富的代谢物，通过补充ω-3-酸乙酯处方Lovaza™在人体中产生。在饮食诱导和遗传性肥胖小鼠模型中，CMPF治疗可逆转肝脏脂质积累。在高脂饮食喂养之前，CMPF治疗通过fgf21依赖机制防止脂肪变性的发展。在这里，我们确定CMPF是人类补充ω-3-酸乙酯的重要代谢物。在肥胖小鼠中，CMPF治疗逆转了肝脏脂质积累并改善了胰岛素敏感性，而在高脂肪饮食喂养之前对瘦小鼠进行治疗可以防止脂肪肝和胰岛素抵抗的发展。我们发现，CMPF能显著提高脂肪酸利用，降低肝脏脂质合成，而这种预防作用依赖于FGF21， FGF21增强了CMPF激活的反馈回路。因此，CMPF可能有助于改善与鱼油补充相关的代谢作用。
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. CMPF is an abundant metabolite resultant from supplementation with the ω-3-acid ethyl ester prescription Lovaza™ in humans Treatment with CMPF reverses hepatic lipid accumulation in diet-induced and genetically obese mouse models CMPF treatment prior to high fat diet feeding prevents development of steatosis through an FGF21-dependent mechanism Fish oil is commonly prescribed for treating dyslipidemia and metabolic syndrome. Here, we identify CMPF as a significant metabolite in humans supplemented with ω-3-acid ethyl esters. CMPF treatment reversed liver lipid accumulation and improved insulin sensitivity in obese mice, while treatment of lean mice prior to high fat diet feeding prevented the development of fatty liver and insulin resistance. We find that CMPF acutely enhances fatty acid utilization and decreases lipid synthesis in the liver, while the preventative action is dependent on FGF21, which potentiates a feedback loop activated by CMPF. Thus, CMPF may contribute to the improved metabolic effects associated with fish oil supplementation.
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影响因子：
64.5
作者：
Cao H;Gerhold K;Mayers JR;Wiest MM;Watkins SM;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
7.1
作者：
Djousse, Luc;Gaziano, J. Michael;Lee, I-Min
通讯作者：
Lee, I-Min
影响因子：
39.2
作者：
GLAUBER, H;WALLACE, P;BRECHTEL, G
通讯作者：
BRECHTEL, G
影响因子：
7.1
作者：
BONAA, KH;BJERVE, KS;NORDOY, A
通讯作者：
NORDOY, A
影响因子：
7.1
作者：
Chen, C. H.;Wu, Kai;Li, Shengtao
通讯作者：
Li, Shengtao