Overexpression of G Protein-Coupled Receptor 40 Protects Obesity-Induced Cardiomyopathy Through the SIRT1/LKB1/AMPK Pathway
Overexpression of G Protein-Coupled Receptor 40 Protects Obesity-Induced Cardiomyopathy Through the SIRT1/LKB1/AMPK Pathway
复制标题
G 蛋白偶联受体 40 的过表达通过 SIRT1/LKB1/AMPK 途径保护肥胖诱发的心肌病
DOI：
10.1089/hum.2021.176
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发表时间：
2022-04-18
影响因子：
4.2
通讯作者：
Dong, Bo
中科院分区：
文献类型：
--
作者：
Li, Sheng-Nan;Yu, Ya-Lin;Dong, Bo
肥胖已经成为一个严重的全球公共卫生问题，由肥胖引起的心肌病最近也得到了关注。G蛋白偶联受体40(GPR40)是参与糖脂代谢的重要蛋白质，在某些疾病模型中具有心脏保护作用。本研究旨在探讨GPR40在肥胖性心肌病中是否起到保护作用。用高脂饲料喂养大鼠建立肥胖模型，用棕榈酸刺激H9c2细胞，模拟高脂刺激。GPR40的过表达是通过感染慢病毒或cDNA质粒实现的。肥胖诱导的心脏损伤模型表现为心功能不全、心肌肥厚和胶原沉积，并伴有炎症、氧化应激和细胞凋亡的增加。然而，GPR40的过度表达减弱了这些变化。GPR40的抗炎作用可能是通过抑制核因子-kappaB途径实现的，而抗氧化应激可能是通过激活核转录因子-红系2相关因子2途径而发生的。在GPR40抗肥胖心肌病的机制方面，GPR40的过表达不仅激活了SIRT1-LKB1-AMPK通路，而且增强了SIRT1与LKB1的结合。SIRT1小干扰RNA可抑制GPR40过表达的抗纤维化、抗炎、抗氧化应激和抗细胞凋亡作用。总之，GPR40的过表达可能通过SIRT1-LKB1-AMPK通路对肥胖诱导的大鼠心脏损伤具有保护作用。
Obesity has become a serious global public health problem, and cardiomyopathy caused by obesity has recently gained attention. As an important protein involved in glucose and lipid metabolism, G protein-coupled receptor 40 (GPR40) exerts cardioprotective effects in some disease models. This study aimed to explore whether GPR40 plays a protective role in obesity-induced cardiomyopathy. We established an obesity model by feeding rats with a high-fat diet, and H9c2 cells were stimulated with palmitic acid to mimic high fat stimulation. Overexpression of GPR40 was achieved by infection with lentivirus or cDNA plasmids. Obesity-induced cardiac injury models exhibit cardiac dysfunction, myocardial hypertrophy, and collagen accumulation, which are accompanied by increased inflammation, oxidative stress, and apoptosis. However, GPR40 overexpression attenuated these alterations. The anti-inflammatory effect of GPR40 may be by inhibiting the nuclear factor-kappa B pathway, and the antioxidative stress may occur as a result of nuclear transcription factor erythroid 2-related factor 2 pathway activation. In terms of the mechanisms of GPR40 against obese cardiomyopathy, GPR40 overexpression not only activated the sirtuin 1 (SIRT1)-liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway but also enhanced the binding of SIRT1 to LKB1. The antifibrotic, anti-inflammatory, antioxidative stress, and antiapoptotic effects of GPR40 overexpression were inhibited by SIRT1 small interfering RNA. In conclusion, GPR40 overexpression protects against obesity-induced cardiac injury in rats, possibly through the SIRT1-LKB1-AMPK pathway.