Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-/VLCAD pathway
Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-/VLCAD pathway
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二甲双胍通过 AMPK/PPAR-α/VLCAD 途径调节犬心房颤动模型中的脂质代谢。
DOI：
10.1186/s12944-019-1059-7
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发表时间：
2019-05-10
影响因子：
4.5
通讯作者：
Liu, Qiming
中科院分区：
文献类型：
--
作者：
Bai, Fan;Liu, Yaozhong;Liu, Qiming
背景：脂质代谢重构在心房颤动（AF）过程中起着至关重要的作用。心肌细胞中异常的脂肪酸（FA）代谢参与了房颤的发病机制。MET（二甲双胍），一种AMPK （amp活化蛋白激酶）激活剂，已被发现与2型糖尿病患者房颤风险降低有关。然而，具体的机制尚不清楚。方法15只杂种犬分为3组：SR组、ARP组（起搏前800次/min，持续6h）、ARP + MET组（起搏前2周给予MET (100mg/kg/d)）。我们评估了代谢因素、循环生化代谢物（底物和产物）的限速酶、心房电生理和脂滴的积累。结果AMPK在ARP组表达升高，MET+ARP组表达明显高于SR组。在ARP组中，PPAR？PGC-1、VLCAD下调，游离脂肪酸、甘油三酯浓度升高，左心耳脂质沉积增多。此外，在此过程中也发现了AERP和AERPd的异常。在接受ARP之前用MET预处理可以逆转上述变化。结论ARP组LAA中FA代谢发生改变，主要表现为限速酶表达异常。二甲双胍通过AMPK/PPAR-/VLCAD途径部分降低AF模型脂质积累，促进FA氧化。我们的研究表明MET可能抑制AF中FA脂质代谢重塑。
BackgroundAtrial lipid metabolic remodeling is critical for the process of atrial fibrillation (AF). Abnormal Fatty acid (FA) metabolism in cardiomyocytes is involved in the pathogenesis of AF. MET (Metformin), an AMPK (AMP-activated protein kinase) activator, has been found to be associated with a decreased risk of AF in patients with type 2 diabetes. However, the specific mechanism remains unknown.MethodsFifteen mongrel dogs were divided into three groups: SR, ARP (pacing with 800 beats/min for 6h), ARP plus MET (treated with MET (100mg/kg/day) for two weeks before pacing). We assessed metabolic factors, speed limiting enzymes circulating biochemical metabolites (substrates and products), atrial electrophysiology and accumulation of lipid droplets.ResultsThe expression of AMPK increased in the ARP group and significantly increased in the MET+ARP group comparing to the SR group. In the ARP group, the expressions of PPAR?PGC-1 and VLCAD were down-regulated, while the concentration of free fatty acid and triglyceride and the lipid deposition in LAA (left atrial appendage) increased. Moreover, AERP and AERPd have also been found abnormally in this process. Pretreatment with MET before receiving ARP reversed the alterations aforementioned.ConclusionsThe FA metabolism in LAA is altered in the ARP group, mainly characterized by the abnormal expression of the rate-limiting enzyme. Metformin reduces lipid accumulation and promotes -oxidation of FA in AF models partially through AMPK/PPAR-/VLCAD pathway. Our study indicates that MET may inhibit the FA lipid metabolic remodeling in AF.