Regulation of mitochondrial metabolism by SIRT4

描述（由申请人提供）：衰老是代谢性疾病的主要风险因素，并导致脂肪酸氧化下降，但这种关联的分子机制仍不清楚。蛋白质Sir 2（沉默信息调节器）积极调节模型生物的衰老，其NAD依赖性酶活性将寿命与代谢联系起来。哺乳动物有七种Sir 2同源物（sirtuins; SIRT 1 -7），它们调节代谢的不同方面。我们先前发现SIRT 4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，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，调节线粒体生物能量学，以及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的假设。然后，我们将研究SIRT 4对线粒体从氨基酸和脂肪酸产生能量的影响。其次，我们将研究SIRT 4介导脂肪酸氧化调节的机制。第三，我们将利用SIRT 4基因敲除小鼠来测试SIRT 4在哺乳动物寿命中的作用，以及在衰老和代谢应激期间调节脂肪酸氧化的作用。这些研究可能为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节仍然知之甚少。该提案研究了SIRT 4作为脂肪酸氧化抑制剂的作用，其可能介导衰老和代谢功能障碍期间脂肪代谢的变化。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.