Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210006, China.
School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China.
Cell Biol Toxicol. 2023 Aug;39(4):1489-1507. doi: 10.1007/s10565-022-09735-z. Epub 2022 Jul 7.
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.
SIRT6（沉默信息调节因子 6）参与调节葡萄糖和脂质的动态平衡。然而，SIRT6 在肥胖相关脂毒性引起的心脏发病机制中的作用仍有待揭示。本研究旨在阐明 SIRT6 在营养过载诱导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。在这项研究中，我们使用 Sirt6 心脏特异性敲除小鼠模型进行高脂肪饮食（HFD）喂养，以探索 SIRT6 在 HFD 诱导肥胖期间心脏组织中的功能和机制。我们还利用新生心肌细胞在体外研究 HFD 诱导损伤过程中 SIRT6 的作用及其下游分子，评估细胞内氧化应激和线粒体含量。我们观察到，在 HFD 诱导肥胖期间，Sirt6 功能丧失加重了心脏损伤，包括左心室肥大和脂质积累。我们的结果表明，在脂肪酸摄取增加的情况下，SIRT6 正向调节内切核酸酶 G（ENDOG）的表达，ENDOG 是一种驻留在线粒体中的分子，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 正向调节超氧化物歧化酶 2（SOD2）的转录后表达。本研究为 SIRT6 在心肌细胞中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 可减少由高脂肪饮食诱导的肥胖引起的心脏内的细胞内氧化应激，涉及对 ENDOG/SOD2 的控制。
