Genetic Discovery of New Regulators of Fatty Acid Synthesis

描述(由申请人提供)：脂肪储存的调节对代谢性疾病、肥胖症甚至癌症具有重要意义。脂肪酸直接来自饮食脂肪的吸收，或通过从头合成将消化的营养物质转化为脂肪酸。我们开发了一种13C同位素标记方法来定量线虫的脂肪酸合成，并应用这一策略通过线虫的遗传学来发现脂肪酸合成的调节因素。这个应用程序的目标是更彻底地描述我们屏幕中识别的两种新机制。首先，我们将研究一种名为HLS-1的II型PI3K，人们对II型PI3K在蠕虫或哺乳动物中的代谢作用知之甚少。我们的初步数据显示，HLS-1是线虫脂肪生成的强大调节者，可能是通过参与胰岛素信号通路中以前未描述的分支来实现这一点的。我们将直接验证这一假说，并更彻底地确定HLS-1对脂代谢的下游调节作用。其次，我们揭示了氧化磷酸化和脂肪酸合成之间有趣的关系。特别是，线粒体呼吸的抑制会导致脂肪酸合成和脂肪储存的强烈增加。这一观察结果不仅对代谢性疾病有影响，还可能解释脂肪酸合成在癌症中的关键作用。这项建议的第二个目标是利用遗传和生化方法来阐明线粒体呼吸影响脂肪生成的机制，特别是测试脂肪酸合成在低氧癌细胞环境中维持氧化还原平衡的模型。 与公众健康相关：脂肪储存取决于膳食脂肪摄入量、脂肪合成和脂肪支出之间的平衡。因此，这些过程中的任何一个过程的调节都可能对代谢性疾病和肥胖症产生重大影响。我们利用线虫的遗传优势，找到了全新的脂肪酸合成调节剂，这些调节剂可以作为治疗肥胖和代谢性疾病的重要靶点。在这项应用中，我们将进行实验，以更彻底地表征这些新型调节剂如何在脂肪合成和储存中发挥作用。

DESCRIPTION (provided by applicant): The regulation of fat storage has considerate implications for metabolic disease, obesity, and even cancer. Fatty acids are obtained directly from absorption of dietary fats, or from conversion of digested nutrients to fatty acids via de novo synthesis. We developed a 13C isotope-labeling assay to quantify fatty acid synthesis in nematodes and applied this strategy to discover regulators of fatty acid synthesis via C. elegans genetics. The objective of this application is to more thoroughly characterize two novel mechanisms identified in our screen. First, we will investigate a type II PI3K called HLS-1, little is known about the metabolic role of type II PI3Ks in worms or mammals. Our preliminary data show that HLS-1 is a strong regulator of lipogenesis in C. elegans, and may do so by participating in a previously uncharacterized branch of the insulin signaling pathway. We will directly test this hypothesis and more thoroughly establish the downstream regulatory effects of HLS-1 on lipid metabolism. Second, we uncovered an intriguing relationship between oxidative phosphorylation and fatty acid synthesis. In particular, inhibition of mitochondrial respiration leads to strong elevation of fatty acid synthesis and lipid storage. This observation not only has implications for metabolic disease, but may also explain the critical role of fatty acid synthesis in cancer. The second objective of this proposal is to exploit genetic and biochemical approaches to elucidate the mechanism by which mitochondrial respiration impacts lipogenesis, testing in particular, a model whereby fatty acid synthesis maintains redox balance in hypoxic cancer cell environments. PUBLIC HEALTH RELEVANCE: Fat storage is determined by a balance between dietary fat intake, fat synthesis, and fat expenditure. Consequently, regulators of any of these processes are likely to be of significant interest to metabolic disease and obesity. We have exploited the genetic advantages of C. elegans to identify completely novel regulators of fatty acid synthesis, regulators that could serve as important targets for treating obesity and metabolic disease. In this application, we will carry out experiments to more thoroughly characterize how these novel regulators impart their effects on fat synthesis and storage.