Tissue-specific regulation of SIRT1 by calorie restriction
Tissue-specific regulation of SIRT1 by calorie restriction
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DOI：
10.1101/gad.1650608
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发表时间：
2008-07-01
影响因子：
10.5
通讯作者：
Guarente, Leonard
中科院分区：
文献类型：
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作者：
Chen, Danica;Bruno, Joanne;Guarente, Leonard
据报道，热量限制（CR）可提高小鼠、大鼠和人类体内的SIRT1蛋白水平，而且SIRT1同源物活性的升高可延长酵母、线虫和果蝇的寿命。在本研究中，我们通过证明肝脏中这种去乙酰化酶的活性实际上因热量限制而降低，因高热量饮食而激活，从而对热量限制在所有组织中诱导SIRT1活性这一范式提出了质疑。我们通过检测SIRT1及其小分子调节剂NAD和NADH的水平，以及评估不同饮食条件下肝脏特异性SIRT1基因敲除小鼠的表型，证明了这一变化。我们的研究结果表明，设计以SIRT1为靶点的热量限制模拟物以提供统一的全身性益处可能比目前想象的更为复杂。
Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.