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、肥胖甚至癌症都有一定的影响。脂肪酸可直接从膳食脂肪的吸收中获得，或通过从头合成将消化的营养素转化为脂肪酸。我们开发了一种13C同位素标记法来定量线虫的脂肪酸合成，并应用该方法通过秀丽隐杆线虫遗传学发现脂肪酸合成的调节因子。本应用程序的目的是更彻底地描述我们在屏幕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。我们的初步数据表明，HLS-1是秀丽隐杆线虫脂肪生成的强大调节剂，可能是通过参与胰岛素信号通路的一个以前未被表征的分支来实现的。我们将直接验证这一假设，更彻底地确立HLS-1对脂质代谢的下游调控作用。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，抑制线粒体呼吸导致脂肪酸合成和脂质储存的强烈升高。这一发现不仅对代谢性疾病有意义，而且还可能解释脂肪酸合成在癌症中的关键作用。本提案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缺氧癌细胞环境中维持氧化还原平衡的模型。

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.