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

线粒体丙酮酸载体-柠檬酸载体轴对肝脏脂肪生成的调节

• 批准号: 9470578
• 负责人: Ryan Douglas Sheldon
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2019-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470578
• 关键词: Address; Anabolism; Bypass; CRISPR/Cas technology; Carbohydrates; Carbon; Cardiovascular Diseases; Cholesterol; Chronic; Citrates; Citric Acid Cycle; Coin; Coupled; Cytosol; Data; Development; Diabetes Mellitus; Diet; Disease; Disease Resistance; Dyslipidemias; Ensure; Environment; Enzymes; Equilibrium; Fasting; Fatty Acids; Fatty Liver; Glucose; Glycolysis; Goals; Health; Hepatic; Hormonal; Human; Hyperlipidemia; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Link; Lipids; Liver; Metabolic; Metabolism; Mission; Mitochondria; Mitochondrial Matrix; Modeling; Modernization; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Overnutrition; Oxaloacetates; Oxides; Phenotype; Production; Public Health; Pyruvate; Regulation; Research; Role; Route; Serum; Source; System; Technology; Testing; Tracer; United States National Institutes of Health; base; carbohydrate metabolism; citrate carrier; energy balance; genome editing; improved; in vivo; innovation; lipid biosynthesis; metabolomics; mitochondrial metabolism; non-alcoholic fatty liver; novel; nutrition; pyruvate carrier; trafficking

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.

项目摘要 脂肪酸和胆固醇的异常肝DE从头合成是血清高脂血症的主要因素 在肥胖和2型糖尿病中。碳水化合物是脂肪生成的主要碳源。柠檬酸盐，生成 线粒体基质占据了一个关键节点，将碳水化合物的可用性与脂肪生成联系起来。这 线粒体丙酮酸载体（MPC）丙酮酸的柠檬酸合成和线粒体的丙酮酸的门矩阵入口 柠檬酸盐载体（CIC）控制其出口到细胞质的脂肪生成。在这里，我们提出了一种新颖的MPC-CIC 通过调节和细胞分布来控制葡萄糖衍生的碳的通量，以脂肪形成 柠檬酸盐。我们的初步数据表明，MPC的肝脏特异性损失已降低了丙酮酸的通量 柠檬酸盐和改善血清脂质。此外，我们还产生了新型的CIC肝脏特异性敲除小鼠。最初的 表征表明，这些小鼠降低了血清胆固醇，与其促脂蛋白一致 角色。该应用的总体目标是描述MPC-CIC轴控制的机制 T2D中的肝脂肪形成。该目标将通过追求两个具体目标来解决：（1）确定 MPC-CIC轴对T2D和（2）中肝脂肪生成的贡献，以确定调节 MPC-CIC轴通过营养激素状态。 AIM 1中的研究将检验MPC-CIC的假设 驱动过量的脂肪生成，并导致T2D中血清血脂异常。 AIM 2中的研究将测试 假设（1）CIC的活性是由葡萄糖和胰岛素调节的，（2） 底物可以绕过MPC-CIC轴的调节节点，以部分维持脂肪生成。这项研究是 意义重大，因为成功完成将提供有关线粒体作用的关键信息 肥胖相关血脂异常的载体系统。这项研究具有创新性，因为它将是第一个 研究在体内检查CIC并研究MPC-CIC轴在肝脂肪生成中的作用。我们期望这一点 这些研究将描述一种新的范式，以了解肥胖症的血脂症。