Regulation of lipogenesis by TCA cycle metabolism

项目概要： 脂肪生成是正常生理所必需的，其失调是肥胖、糖尿病、 心血管疾病、癌症、神经变性和感染。经典从头调节 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激活的碳水化合物传感。然而，这两个方案都不方便 底物处理也不设置细胞能量状态以适应脂肪生成条件。线粒体， 特别是TCA循环，是用于脂质合成但在转运之前的乙酰辅酶A的假定来源 在细胞质中，它被转化为柠檬酸盐，这是消耗TCA循环中间产物的一个步骤。余额 在TCA循环分解（TCA循环中间产物的损失）和回补（TCA的补充）之间 循环中间体），并可能有助于确定柠檬酸盐可用于脂质合成的速率。 已知这些途径在许多疾病中被破坏，这些疾病也具有病理性脂质代谢。 因此，我们将研究如何回补和cataplerotic途径的TCA循环有助于介导 通过促进底物（例如柠檬酸盐）的可用性和/或细胞对营养的适当脂肪生成反应 脂肪生成反应所需的能量状态。我们将使用最先进的稳定同位素示踪剂， 化学平台和小鼠遗传学，以评估这些途径在控制脂质代谢率中的作用。 合成.该项目的完成将确定新的代谢机制的调节脂质 合成补充转录机制，并可能具有特别的相关性， 已知破坏TCA循环代谢的疾病列表。

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.