The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.

Sirtuin 6 (SIRT6) 参与调节葡萄糖和脂质稳态。然而，SIRT6在肥胖相关脂毒性引起的心脏发病机制中的功能仍有待揭示。本研究旨在阐明SIRT6在营养超载所致肥胖引起的心脏损伤发病机制中的作用，并探讨影响心脏氧化应激的下游信号通路。在本研究中，我们使用高脂饮食（HFD）喂养的Sirt6心脏特异性基因敲除小鼠模型来探讨SIRT6在HFD诱导的肥胖期间心脏组织中的功能和机制。我们还利用新生儿心肌细胞研究了 SIRT6 在 HFD 诱导的体外损伤过程中的作用和下游分子，其中评估了细胞内氧化应激和线粒体含量。我们观察到，在 HFD 诱导的肥胖期间，Sirt6功能丧失会加重心脏损伤，包括左心室肥厚和脂质堆积。我们的结果证明，在脂肪酸摄取增加时，SIRT6 正向调节核酸内切酶 G (ENDOG) 的表达，这是一种线粒体驻留分子，在线粒体生物发生和氧化还原稳态中发挥重要作用。我们的结果还表明，SIRT6 通过 ENDOG 在转录后正向调节超氧化物歧化酶 2 (SOD2) 表达。我们的研究为 SIRT6 在心肌细胞线粒体生物发生中的有益作用提供了新的视角。我们的数据还表明，SIRT6 是减少高脂饮食引起的肥胖引发的心脏细胞内氧化应激所必需的，涉及 ENDOG/SOD2 的控制。