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，并导致脂肪酸氧化减少，但这种联系的分子机制仍不清楚。在模式生物中，Sir2(沉默信息调节蛋白)积极调节衰老，其依赖于NAD的酶活性将寿命与新陈代谢联系起来。哺乳动物有七个Sir2同源基因(sirtuins；SIRT1-7)，它们调节新陈代谢的不同方面。我们先前发现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，这可能涉及几个机制，包括抑制线粒体GDH活性，调节线粒体生物能量学，以及转录抑制参与脂肪酸分解代谢的基因。我们将通过包括老鼠生物学、化学和生物化学在内的多学科方法来检验这一假说。首先，使用SIRT4 KO小鼠的原代肝细胞，我们将检验SIRT4直接抑制脂肪酸氧化的假设。然后，我们将研究SIRT4对氨基酸和脂肪酸产生线粒体能量的影响。其次，我们将研究SIRT4调节脂肪酸氧化的机制。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。这些研究可能对衰老过程中脂肪酸氧化的分子调控提供重要的见解。与公共健康相关：对脂肪酸氧化随年龄下降的调节仍知之甚少。这项建议研究了SIRT4作为脂肪酸氧化抑制因子的作用，这可能介导了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疗法。

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.