Activation of cardiac AMPK-FGF21 feed-forward loop in acute myocardial infarction: Role of adrenergic overdrive and lipolysis byproducts
Activation of cardiac AMPK-FGF21 feed-forward loop in acute myocardial infarction: Role of adrenergic overdrive and lipolysis byproducts
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DOI：
10.1038/s41598-019-48356-1
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发表时间：
2019-08-14
影响因子：
4.6
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Sunaga, Hiroaki;Koitabashi, Norimichi;Kurabayashi, Masahiko
成纤维细胞生长因子21（FGF 21）是具有抗氧化和抗肥大作用的代谢激素。然而，急性心肌梗死（AMI）期间FGF 21表达的调节仍不清楚。我们检测了50例AMI患者和43例稳定型心绞痛（sAP）患者的血液样本中的FGF 21、脂肪酸结合蛋白4（FABP 4）（一种响应肾上腺素能脂解信号的脂肪细胞分泌的蛋白质）以及总脂肪酸和单个脂肪酸。与sAP患者相比，AMI患者入院时血清FGF 21水平较高，与FABP 4峰值和饱和脂肪酸（SFA）峰值显著相关，而与心肌肌钙蛋白T峰值无相关性。在小鼠中，心肌缺血快速诱导心脏产生FGF 21，这伴随着AMP激活蛋白激酶（AMPK）依赖性途径的激活。与AMPK激活剂AICAR一样，儿茶酚胺（去甲肾上腺素和异丙肾上腺素）和SFA（棕榈酸酯和硬脂酸酯）通过AMPK激活显著增加心肌细胞的FGF 21产生和释放。重组FGF 21诱导其自身的表达以及参与心肌细胞代谢稳态和线粒体生物发生的AMPK下游靶点成员的表达。这些发现表明，肾上腺素能受体激动剂和由此产生的脂肪组织脂解诱导心脏AMPK-FGF 21前馈回路，其潜在地提供针对缺血性损伤的心脏保护。
Fibroblast growth factor 21 (FGF21) is a metabolic hormone having anti-oxidative and anti-hypertrophic effects. However, the regulation of FGF21 expression during acute myocardial infarction (AMI) remains unclear. We tested blood samples from 50 patients with AMI and 43 patients with stable angina pectoris (sAP) for FGF21, fatty acid binding protein 4 (FABP4), a protein secreted from adipocytes in response to adrenergic lipolytic signal, and total and individual fatty acids. Compared with sAP patients, AMI patients had higher serum FGF21 levels on admission, which were significantly correlated with peak FABP4 and saturated fatty acids (SFAs) but not with peak levels of cardiac troponin T. In mice, myocardial ischemia rapidly induced FGF21 production by the heart, which accompanied activation of AMP-activated protein kinase (AMPK)-dependent pathway. Like AICAR, an activator of AMPK, catecholamines (norepinephrine and isoproterenol) and SFAs (palmitate and stearate) significantly increased FGF21 production and release by cardiac myocytes via AMPK activation. Recombinant FGF21 induced its own expression as well as members of down-stream targets of AMPK involved in metabolic homeostasis and mitochondrial biogenesis in cardiac myocytes. These findings suggest that adrenergic overdrive and resultant adipose tissue lipolysis induce cardiac AMPK-FGF21 feed-forward loop that potentially provides cardioprotection against ischemic damage.