Regulation of lipogenesis by TCA cycle metabolism

项目总结： 脂肪生成是正常生理所必需的，它的失调是肥胖、糖尿病、 心血管疾病、癌症、神经变性和感染。从头开始的经典规则 脂肪生成涉及通过激素介导的SREBP对脂肪生成基因表达的转录调节 激活，和/或通过ChREBP激活的碳水化合物感觉。然而，这两个程序都不利于 底物处理也不会设置细胞能量状态，使其服从于产脂条件。线粒体， 具体地说，TCA循环是用于脂质合成的乙酰辅酶A的假定来源，但在运输之前 到胞浆中，它被转化为柠檬酸盐，这是消耗三氯乙酸循环中间体的一个步骤。余额 在三氯乙烷循环诱变(三氯乙烷循环中间体的损失)和恢复(三氯乙烷补充)之间 循环中间体)，并可帮助确定柠檬酸盐用于脂质合成的速率。 已知这些途径在许多疾病中被破坏，这些疾病也有病理性的脂类代谢。 因此，我们将研究TCA循环的退行性和退行性途径如何帮助调节 通过促进底物(例如柠檬酸盐)的利用和/或细胞，对营养作出适当的生脂反应 脂肪生成反应所必需的能量状态。我们将使用最先进的稳定同位素示踪剂，分析 化学平台和小鼠遗传学评估这些途径在控制血脂速率中的作用 综合。该项目的完成将确定调节脂质的新的代谢机制 补充转录机制的合成，可能与生长发育有特殊的相关性 已知会扰乱三氯乙烷循环代谢的疾病清单。

Project Summary: Lipogenesis is essential for normal physiology and its dysregulation is a notable feature of obesity, diabetes, cardiovascular disease, cancer, neurodegeneration and infection. Classical regulation of de novo lipogenesis involves transcriptional regulation of lipogenic gene expression via hormone mediated SREBP activation, and/or carbohydrate sensing via ChREBP activation. However, neither program facilitates substrate handling nor set the cellular energy status amenable to lipogenic conditions. The mitochondria, specifically the TCA cycle, is the putative source of acetyl-CoA used for lipid synthesis but before transport to the cytosol, it is converted to citrate, a step that consumes TCA cycle intermediates. The balance between TCA cycle cataplerosis (loss of TCA cycle intermediates) and anaplerosis (replenishment of TCA cycle intermediates) and may help to determine the rate at which citrate can be used for lipid synthesis. These pathways are known to be disrupted in many diseases, that also have pathological lipid metabolism. Thus, we will examine how anaplerotic and cataplerotic pathways of the TCA cycle help to mediate the appropriate lipogenic response to nutrition, by promoting substrate (e.g. citrate) availability and/or cellular energy status necessary for lipogenic reactions. We will use state of the art stable isotope tracers, analytical chemistry platforms and mouse genetics to evaluate the role of these pathways in controlling rates of lipid synthesis. Completion of this project will identify new metabolic mechanisms for the regulation of lipid synthesis that complement transcriptional mechanisms and may have particular relevance to the growing list of diseases known to disrupt TCA cycle metabolism.