Regulation of mitochondrial metabolism by SIRT4

项目摘要 衰老是代谢疾病的主要危险因素，并导致脂肪酸氧化下降，但 这种关联的分子机制仍不清楚。沉默信息调节器（Silent Information Regulator） 在模型生物中积极调节衰老，其NAD依赖性酶活性与寿命相关 新陈代谢。哺乳动物有七种Sir 2同源物（sirtuins; SIRT 1 -7），它们调节哺乳动物的不同方面。 新陈代谢.我们以前发现SIRT 4通过抑制蛋白质的表达来调节氨基酸代谢。 谷氨酸脱氢酶（GDH）。我们的新结果表明SIRT 4抑制脂肪酸代谢， 这可能涉及几种机制，包括抑制线粒体中的GDH活性， 线粒体生物能量学和参与脂肪酸代谢的基因的转录抑制。我们将 通过多学科的方法来测试这一假设，包括小鼠生物学，化学和 生物化学首先，使用来自SIRT 4 KO小鼠的原代肝细胞，我们将检验SIRT 4 直接抑制脂肪酸氧化。然后，我们将研究SIRT 4对线粒体能量的影响， 从氨基酸和脂肪酸生产。其次，我们将研究介导 通过SIRT 4调节脂肪酸氧化。第三，我们将利用SIRT 4 KO小鼠来测试SIRT 4在以下中的作用： 哺乳动物的寿命和在老化和代谢应激期间的脂肪酸氧化的调节。这些 这些研究可能对衰老过程中脂肪酸氧化的分子调节提供重要的见解。

Project Summary Aging is a major risk factor for metabolic disease and results in a decline in fatty acid oxidation, but the molecular mechanisms for this association are still unclear. The protein Sir2 (Silent Information Regulator) positively regulates aging in model organisms, and its NAD-dependent enzymatic activity connects lifespan with metabolism. Mammals have seven Sir2 homologs (sirtuins; SIRT1-7), which regulate distinct aspects of metabolism. We previously discovered that SIRT4 regulates amino acid metabolism via the inhibition of glutamate dehydrogenase (GDH). Our new results suggest that SIRT4 suppresses fatty acid metabolism, which likely involves several mechanisms, including inhibition of GDH activity in mitochondria, regulation of mitochondrial bioenergetics, and transcriptional repression of genes involved in fatty acid catabolism. We will test this hypothesis through a multi-disciplinary approach, including mouse biology, chemistry and biochemistry. First, using primary hepatocytes from SIRT4 KO mice, we will test the hypothesis that SIRT4 directly suppresses fatty acid oxidation. Then, we will investigate the effect of SIRT4 on mitochondrial energy production from amino acids and fatty acids. Second, we will investigate mechanisms that mediate the regulation of fatty acid oxidation by SIRT4. Third, we will utilize SIRT4 KO mice to test the role of SIRT4 in mammalian lifespan and in the regulation of fatty acid oxidation during aging and metabolic stress. These studies may provide important insights into the molecular regulation of fatty acid oxidation during aging.