Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity.
Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity.
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通过左旋肉碱增强脂肪酸氧化，通过激活 AMPK 信号传导和减轻心脏脂毒性来减轻肥胖相关的心房颤动和结构重塑
DOI：
10.3389/fphar.2021.771940
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zheng Q
中科院分区：
文献类型：
--
作者：
Zhang Y;Fu Y;Jiang T;Liu B;Sun H;Zhang Y;Fan B;Li X;Qin X;Zheng Q
心房颤动（AF）是临床上最常见的持续性心律失常。其发病机制与代谢紊乱有关，尤其是脂肪酸氧化缺陷（FAO）。然而，推广FAO是否可以预防AF的发生和发展仍然是一个谜。在这项研究中，我们通过高脂饮食（HFD）喂养建立了肥胖相关的AF小鼠模型，并使用左旋肉碱（LCA，150 mg/kg体重/d），肉毒碱棕榈酰转移酶-1B（CPT 1B; FAO的限速酶）的内源性辅因子，以研究FAO促进是否可以减轻肥胖AF的易感性。所有小鼠均接受心房易损性的电生理评估，以及AF底物和潜在机制的超声心动图、组织学和分子评价，并通过体外药理学实验进一步验证。HFD诱导的肥胖小鼠增加AF脆弱性并表现出明显的心房结构重构，包括左心房扩张、心肌细胞肥大、连接蛋白-43重构和纤维化。在病理学上，HFD明显导致心脏FAO缺陷和随后的脂毒性，从而引起一系列病理反应，包括氧化应激、DNA损伤、炎症和胰岛素抵抗。通过LCA增强FAO可减弱肥胖小鼠心房的脂毒性和脂毒性诱导的病理变化，从而恢复结构重塑并改善AF易感性。从机制上讲，LCA在体内和体外激活AMPK/PGC 1 α信号传导，并且通过化合物C对AMPK的药理学抑制减弱了棕榈酸酯处理的原代心房心肌细胞中LCA诱导的心脏保护。综上所述，我们的结果表明，通过LCA促进FAO通过激活AMPK信号和减轻心房脂毒性来减弱肥胖介导的AF和结构重塑。因此，增强FAO可能是AF的潜在治疗靶点。
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.
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