Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India.
Tata Institute of Fundamental Research, Colaba, Mumbai, India.
J Cell Physiol. 2018 Jul;233(7):5478-5489. doi: 10.1002/jcp.26434. Epub 2018 Feb 22.
Sirtuins are a family of enzymes, which govern a number of cellular processes essential for maintaining physiological balance. SIRT6, a nuclear sirtuin, is implicated in the development of metabolic disorders. The role of SIRT6 in regulation of cardiac metabolism is unexplored. Although glucose is not the primary energy source of heart, defects in glucose oxidation have been linked to heart failure. SIRT6 mice hearts exhibit increased inhibitory phosphorylation of PDH subunit E1α. SIRT6 deficiency enhances FoxO1 nuclear localization that results in increased expression of PDK4. We show that SIRT6 transcriptionally regulates the expression of PDK4 by binding to its promoter. SIRT6 hearts show accumulation of lactate, indicating compromised mitochondrial oxidation. SIRT6 deficiency results in decreased oxygen consumption rate and concomitantly lesser ATP production. Mechanistically, SIRT6 deficiency leads to increased FoxO1-mediated transcription of PDK4. Our findings establish a novel link between SIRT6 and cardiac metabolism, suggesting a protective role of SIRT6 in maintaining cardiac homeostasis.
去乙酰化酶 Sirtuins 是一类调节细胞过程的酶，对于维持生理平衡至关重要。Sirtuin6（SIRT6）是一种核去乙酰化酶，与代谢紊乱的发生有关。SIRT6 在心脏代谢调节中的作用尚不清楚。尽管葡萄糖不是心脏的主要能量来源，但葡萄糖氧化缺陷与心力衰竭有关。SIRT6 缺乏会增加 PDH 亚基 E1α 的抑制性磷酸化。SIRT6 缺乏增强 FoxO1 的核定位，导致 PDK4 的表达增加。我们表明，SIRT6 通过结合其启动子来转录调节 PDK4 的表达。SIRT6 心脏中乳酸的积累表明线粒体氧化受损。SIRT6 缺乏导致耗氧量降低，同时产生的 ATP 减少。从机制上讲，SIRT6 缺乏导致 FoxO1 介导的 PDK4 转录增加。我们的研究结果确立了 SIRT6 与心脏代谢之间的新联系，表明 SIRT6 在维持心脏内稳态方面具有保护作用。
