Regulation of mitochondrial metabolism by SIRT4

描述（申请人提供）：衰老是代谢性疾病的主要危险因素，导致脂肪酸氧化下降，但这种关联的分子机制尚不清楚。Sir2蛋白（Silent Information Regulator，沉默信息调节器）在模式生物中积极调节衰老，其依赖于nad的酶活性将寿命与代谢联系起来。哺乳动物有7种sirr2同源物（sirtuins; SIRT1-7），它们调节新陈代谢的不同方面。我们之前发现SIRT4通过抑制谷氨酸脱氢酶（GDH）来调节氨基酸代谢。我们的新结果表明，SIRT4抑制脂肪酸代谢，可能涉及多种机制，包括抑制线粒体中GDH活性，调节线粒体生物能量，以及参与脂肪酸分解代谢的基因的转录抑制。我们将通过包括小鼠生物学、化学和生物化学在内的多学科方法来验证这一假设。首先，使用SIRT4小鼠的原代肝细胞，我们将验证SIRT4直接抑制脂肪酸氧化的假设。然后，我们将研究SIRT4对线粒体氨基酸和脂肪酸能量产生的影响。其次，我们将研究SIRT4介导脂肪酸氧化调节的机制。第三，我们将利用SIRT4 KO小鼠来测试SIRT4在哺乳动物寿命中的作用，以及在衰老和代谢应激过程中对脂肪酸氧化的调节。这些研究可能为了解衰老过程中脂肪酸氧化的分子调控提供重要的见解。公共卫生相关性：随着年龄的增长，脂肪酸氧化下降的调控机制仍然知之甚少。本研究探讨了SIRT4作为脂肪酸氧化抑制因子的作用，SIRT4可能介导衰老过程中脂肪代谢的变化和代谢功能障碍。这些研究有可能导致饮食和年龄相关代谢综合征的新治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The regulation of declining fatty acid oxidation with age remains poorly understood. This proposal investigates the role of SIRT4, as a suppressor of fatty acid oxidation, which may mediate changes in fat metabolism during aging and metabolic dysfunction. These studies have the potential to lead to new treatments of diet and age-associated metabolic syndrome.