Regulation of lipogenesis by TCA cycle metabolism

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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.