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新合成异常是导致血清高脂血症的主要因素 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，产生于 线粒体基质是连接碳水化合物供应和脂肪生成的关键节点。这个 线粒体丙酮酸载体(MPC)阻断丙酮酸基质进入柠檬酸合成和线粒体 柠檬酸盐载体(CIC)控制其向胞浆中的输出以生成脂肪。在这里，我们提出了一种新的MPC-CIC 通过调节和细胞分布来控制葡萄糖衍生碳流到脂肪生成的轴 柠檬酸盐。我们的初步数据表明，肝脏特异性丢失的MPC减少了丙酮酸流入 柠檬酸和改善血脂。此外，我们还培育了新的CIC肝脏特异性基因敲除小鼠。首字母 特征显示这些小鼠降低了血清胆固醇，这与其促脂肪生成的作用一致。 角色。此应用程序的总体目标是描述MPC-CIC轴控制的机制 T2D的肝脏脂肪生成。这一目标将通过追求两个具体目标来实现：(1)确定 MPC-CIC轴在T2D肝脏脂肪生成中的作用和(2)确定MPC-CIC轴的调节 MPC-CIC轴以营养-激素状态为主。目标1中的研究将检验MPC-CIC的假设 导致过多的脂肪生成，并导致T2D患者的血脂紊乱。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的调节，以及(2)该替代方案 底物可以绕过MPC-CIC轴的调控节点，部分维持脂肪生成。这项研究是 意义重大，因为成功的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携带者系统。这项研究具有创新性，因为它将是第一次 研究体内CIC，并探讨MPC-CIC轴在肝脏脂肪生成中的作用。我们期待着 这些研究将描述一种新的范式来理解肥胖对血脂的影响。

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.