Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
FASEB J. 2019 Oct;33(10):10872-10888. doi: 10.1096/fj.201900767R. Epub 2019 Jul 12.
Sirtuins (Sirts) are implicated in regulating a myriad of biologic functions ranging from cell growth and metabolism to longevity. Here, we show that nuclear Sirt, Sirt6, and mitochondrial Sirt, Sirt3, regulate each other's activity and protect the heart from developing diabetic cardiomyopathy. We found that expression of both Sirt6 and Sirt3 was reduced in cardiomyocytes treated with palmitate and in hearts of mice fed with a high-fat, high-sucrose (HF-HS) diet to develop obesity and diabetes. Conversely, whole-body overexpressing Sirt6 transgenic (Tg.Sirt6) mice were protected from developing obesity and insulin resistance when fed with the same HF-HS diet. The hearts of Tg.Sirt6 mice were also protected from mitochondrial fragmentation and decline of Sirt3, resulting otherwise from HF-HS diet feeding. Mechanistic studies showed that Sirt3 preserves Sirt6 levels by reducing oxidative stress, whereas Sirt6 maintains Sirt3 levels by up-regulating nuclear respiratory factor 2 (Nrf2)-dependent Sirt3 gene transcription. We found that Sirt6 regulates Nrf2-mediated cardiac gene expression in 2 ways; first, Sirt6 suppresses expression of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, and second, Sirt6 binds to Nrf2 and antagonizes its interaction with Keap1, thereby stabilizing Nrf2 levels in cardiomyocytes. Together, these studies demonstrate that Sirt6 and Sirt3 maintain each other's activity and protect the heart from developing diabetic cardiomyopathy.-Kanwal, A., Pillai, V. B., Samant, S., Gupta, M., Gupta, M. P. The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy.
Sirtuins（Sirts）参与调节从细胞生长和代谢到长寿等多种生物学功能。在这里，我们表明核 Sirt6 和线粒体 Sirt3 调节彼此的活性，并保护心脏免受糖尿病性心肌病的发展。我们发现，在用棕榈酸处理的心肌细胞中和在喂食高脂肪、高蔗糖（HF-HS）饮食以发展肥胖和糖尿病的小鼠的心脏中，Sirt6 和 Sirt3 的表达均降低。相反，当喂食相同的 HF-HS 饮食时，全身性过表达 Sirt6 的转基因（Tg.Sirt6）小鼠可免受肥胖和胰岛素抵抗的发展。Tg.Sirt6 小鼠的心脏也免受线粒体片段化和 Sirt3 水平下降的影响，否则会因 HF-HS 饮食喂养而发生这种情况。机制研究表明，Sirt3 通过降低氧化应激来维持 Sirt6 的水平，而 Sirt6 通过上调核呼吸因子 2（Nrf2）依赖性 Sirt3 基因转录来维持 Sirt3 的水平。我们发现 Sirt6 通过 2 种方式调节 Nrf2 介导的心脏基因表达；首先，Sirt6 抑制 Nrf2 的负调节剂 Kelch-like ECH-associated protein 1（Keap1）的表达，其次，Sirt6 与 Nrf2 结合并拮抗其与 Keap1 的相互作用，从而稳定心肌细胞中的 Nrf2 水平。总之，这些研究表明 Sirt6 和 Sirt3 维持彼此的活性，并保护心脏免受发展肥胖介导的糖尿病性心肌病的影响。
