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广泛的意义。脂肪酸直接从膳食脂肪的吸收中获得，或者通过从头合成从消化的营养素转化为脂肪酸。我们开发了一种13 C同位素标记测定法来定量线虫中的脂肪酸合成，并应用该策略来发现通过C. elegans遗传学本申请的目的是更彻底地表征我们筛选中确定的两种新机制。首先，我们将研究一种名为HLS-1的II型PI 3 K，目前人们对II型PI 3 K在蠕虫或哺乳动物中的代谢作用知之甚少。我们的初步数据表明，HLS-1是C.并且可能通过参与胰岛素信号传导途径的先前未表征的分支来这样做。我们将直接测试这一假设，并更彻底地建立HLS-1对脂质代谢的下游调节作用。其次，我们发现了氧化磷酸化和脂肪酸合成之间的有趣关系。特别是，线粒体呼吸的抑制导致脂肪酸合成和脂质储存的强烈升高。这一观察结果不仅对代谢疾病有意义，而且还可以解释脂肪酸合成在癌症中的关键作用。该提案的第二个目标是利用遗传和生物化学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缺氧癌细胞环境中维持氧化还原平衡的模型。 公共卫生相关性：脂肪储存是由膳食脂肪摄入、脂肪合成和脂肪消耗之间的平衡决定的。因此，任何这些过程的调节剂都可能对代谢疾病和肥胖产生重大影响。我们利用了C. elegans发现了全新的脂肪酸合成调节因子，这些调节因子可以作为治疗肥胖和代谢疾病的重要靶点。在本申请中，我们将进行实验，以更彻底地表征这些新型调节剂如何影响脂肪合成和储存。

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.