Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling.
Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling.
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DOI：
10.1016/j.cmet.2015.07.028
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发表时间：
2015-10-06
期刊：
影响因子：
29
通讯作者：
Finck BN
中科院分区：
文献类型：
--
作者：
McCommis KS;Chen Z;Fu X;McDonald WG;Colca JR;Kletzien RF;Burgess SC;Finck BN
丙酮酸转运穿过线粒体内膜被认为是肝细胞中肝细胞生成的先决条件，这对于在长期食物剥夺期间维持正常肝细胞是重要的，但也有助于糖尿病中的高血糖。为了确定线粒体丙酮酸输入在胚胎发生中的需要，产生了具有线粒体丙酮酸载体2（LS-Mpc2-/-）的肝脏特异性缺失的小鼠。MPC2的丧失损害了肝细胞丙酮酸代谢、标记的丙酮酸转化为TCA循环中间体和葡萄糖以及丙酮酸产生葡萄糖，但没有完全消除。对禁食LS-Mpc2 −/−小鼠肝脏的无偏倚代谢组学分析表明，氨基酸代谢的改变，包括丙氨酸-丙氨酸循环，可能会弥补MPC2的损失。事实上，抑制丙酮酸-丙氨酸转氨作用进一步降低了LS-Mpc2 −/−肝细胞的线粒体丙酮酸代谢和葡萄糖产生。这些数据证明了MPC 2在控制肝细胞再生中的重要作用，并阐明了一种用于规避线粒体丙酮酸盐输入阻断的补偿机制。
Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite step for gluconeogenesis in hepatocytes, which is important for maintenance of normoglycemia during prolonged food deprivation, but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial pyruvate carrier 2 (LS-Mpc2−/−) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte pyruvate metabolism, labelled pyruvate conversion to TCA cycle intermediates and glucose, and glucose production from pyruvate. Unbiased metabolomic analyses of livers from fasted LS-Mpc2−/− mice suggested that alterations in amino acid metabolism, including pyruvate-alanine cycling, might compensate for loss of MPC2. Indeed, inhibition of pyruvate-alanine transamination further reduced mitochondrial pyruvate metabolism and glucose production by LS-Mpc2−/− hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial pyruvate import.