Regulation of Hepatic Lipogenesis by a Mitochondrial Pyruvate Carrier-Citrate Carrier Axis

项目摘要 肝脏脂肪酸和胆固醇的异常从头合成是血清高脂血症的主要原因 肥胖症和2型糖尿病。碳水化合物是脂肪生成的主要碳源。柠檬酸盐，生成于 线粒体基质占据了将碳水化合物的可用性与脂肪生成联系起来的关键节点。的 线粒体丙酮酸载体（MPC）门控丙酮酸基质进入柠檬酸盐合成， 柠檬酸盐载体（CIC）控制其输出到胞质溶胶用于脂肪生成。在这里，我们提出了一种新的MPC-CIC， 通过调节和细胞分布控制葡萄糖衍生碳流向脂肪生成的轴 柠檬酸盐。我们的初步数据表明，肝脏特定的MPC损失减少了丙酮酸流入 柠檬酸盐和改善血脂。此外，我们已经产生了新的CIC肝特异性敲除小鼠。初始 表征表明，这些小鼠具有降低的血清胆固醇，与其促脂肪生成相一致。 作用本申请的总体目标是描绘MPC-CIC轴控制的机制 2型糖尿病肝脏脂肪生成这一目标将通过追求两个具体目标来实现：（1）确定 MPC-CIC轴对T2 D中肝脏脂肪生成的贡献;（2）为了确定MPC-CIC轴对T2 D中肝脏脂肪生成的调节， MPC-CIC轴按营养-激素状态。目标1中的研究将检验MPC-CIC 驱动过量脂肪生成并导致T2 D中的血清血脂异常。目标2中的研究将测试 假设（1）CIC的活性受葡萄糖和胰岛素调节，以及（2） 底物可以绕过MPC-CIC轴的调节节点以部分维持脂肪生成。本研究是 重要的是，成功完成将提供关于线粒体作用的关键信息， 肥胖相关性血脂异常的载体系统。这项研究是创新的，因为它将是第一个 本研究旨在检查体内CIC并研究MPC-CIC轴在肝脏脂肪生成中的作用。我们预计 这些研究将描述一个新的范例，以了解肥胖症的血脂异常的影响。

Project Summary Aberrant hepatic de novo synthesis of fatty acids and cholesterol is a major contributor to serum hyperlipidemia in obesity and type 2 diabetes. Carbohydrates are a major carbon source for lipogenesis. Citrate, generated in the mitochondrial matrix, occupies a key node linking carbohydrate availability to lipogenesis. The mitochondrial pyruvate carrier (MPC) gates matrix entry of pyruvate for citrate synthesis and the mitochondrial citrate carrier (CIC) controls its export to the cytosol for lipogenesis. Here we propose that a novel MPC-CIC axis that controls the flux of glucose derived carbons to lipogenesis through modulation and cellular distribution of citrate. Our preliminary data indicate that liver specific loss of the MPC have decreased pyruvate flux into citrate and improved serum lipids. In addition, we have generated novel CIC liver specific knockout mice. Initial characterization reveal that these mice have decreased serum cholesterol, consistent with its pro-lipogenic role. The overall goal of this application is to delineate mechanisms through which the MPC-CIC axis controls hepatic lipogenesis in T2D. This goal will be addressed by pursuing two specific aims: (1) To determine the contribution of the MPC-CIC axis to hepatic lipogenesis in T2D and (2) To determine the regulation of the MPC-CIC axis by nutritional-hormonal status. The studies in Aim 1 will test the hypothesis that the MPC-CIC drives excess lipogenesis and contributes to serum dyslipidemia in T2D. The studies in Aim 2 will test the hypothesis that (1) the activity of the CIC is modulated by glucose and insulin, and (2) that alternative substrates can bypass regulatory nodes of the MPC-CIC axis to partially sustain lipogenesis. This research is significant because successful completion will provide critical information on the role of the mitochondrial carrier system in obesity associated dyslipidemia. This research is innovative because the it will be the first study to examine CIC in vivo and investigate a role of the MPC-CIC axis in hepatic lipogenesis. We expect that these studies will describe a new paradigm to understand the dyslipidemic effects of obesity.