Regulation of lipogenesis by TCA cycle metabolism

项目概要： 脂肪生成对于正常生理机能至关重要，其失调是肥胖、糖尿病、 心血管疾病、癌症、神经退行性疾病和感染。从头的经典调控 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 激活进行碳水化合物传感。然而，这两个程序都没有促进 底物处理也不设置适合脂肪生成条件的细胞能量状态。线粒体， 特别是 TCA 循环，是用于脂质合成但在运输之前的乙酰辅酶 A 的推定来源 进入细胞质后，它会转化为柠檬酸盐，这一步骤会消耗 TCA 循环中间体。余额 TCA 循环折返（TCA 循环中间体损失）和回补（TCA 补充）之间 循环中间体），可能有助于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，这些疾病也具有病理性脂质代谢。 因此，我们将研究 TCA 循环的回补和回补途径如何帮助介导 通过促进底物（例如柠檬酸盐）的可用性和/或细胞对营养产生适当的脂肪生成反应 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、分析 化学平台和小鼠遗传学来评估这些途径在控制脂质速率中的作用 合成。该项目的完成将确定脂质调节的新代谢机制 补充转录机制的合成，可能与生长特别相关 已知会破坏 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.