Gerhart-Hines Zachary, Rodgers Joseph T, Bare Olivia, Lerin Carles, Kim Seung-Hee, Mostoslavsky Raul, Alt Frederick W, Wu Zhidan, Puigserver Pere
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA.
EMBO J. 2007 Apr 4;26(7):1913-23. doi: 10.1038/sj.emboj.7601633. Epub 2007 Mar 8.
In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.
在哺乳动物中，食物匮乏期间能量和营养稳态的维持是通过外周组织中线粒体脂肪酸氧化的增加来实现的。驱动这种细胞氧化过程的一个重要成分是转录辅激活因子PGC-1α。在此，我们表明禁食诱导骨骼肌中PGC-1α去乙酰化，并且PGC-1α的SIRT1去乙酰化是线粒体脂肪酸氧化基因激活所必需的。此外，乙酰转移酶GCN5或SIRT1抑制剂烟酰胺的表达诱导PGC-1α乙酰化，并降低肌管中PGC-1α靶基因的表达。与营养剥夺状态下发生的从葡萄糖氧化向脂肪酸氧化的转变一致，SIRT1是响应低葡萄糖浓度诱导和维持脂肪酸氧化所必需的。因此，我们已确定SIRT1是PGC-1α的功能调节因子，其诱导线粒体脂肪酸氧化的代谢基因转录程序。这些结果对于理解选择性营养适应以及它如何影响寿命或肥胖症和糖尿病等代谢疾病具有重要意义。
