Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes.
Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes.
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DOI：
10.1111/febs.13992
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Norton L
中科院分区：
文献类型：
--
作者：
Shannon CE;Daniele G;Galindo C;Abdul-Ghani MA;DeFronzo RA;Norton L
吡格列酮在全球范围内用于治疗2型糖尿病（T2 DM），是改善T2 DM患者葡萄糖稳态和胰岛素抵抗的最有效疗法之一。然而，其在组织中的作用机制和调节葡萄糖代谢的途径尚不完全明确。在这里，我们研究了吡格列酮对肝细胞丙酮酸代谢的直接影响，以及这些观察结果对线粒体丙酮酸转运调控因子MPC 1和MPC 2的依赖性。在培养的H4 IIE肝细胞中，吡格列酮抑制[2- 14 C]-丙酮酸氧化和丙酮酸驱动的耗氧量，在从肝细胞和人骨骼肌分离的线粒体中，吡格列酮选择性和剂量依赖性地抑制丙酮酸驱动的ATP合成。吡格列酮还抑制肝细胞葡萄糖生成（HGP），而不影响关键HGP调控基因的mRNA表达。靶向siRNA沉默MPC 1和2可适度抑制丙酮酸氧化和丙酮酸驱动的ATP合成，但不会改变丙酮酸驱动的HGP，重要的是，它不会影响吡格列酮对任一途径的作用。总之，这些发现概述了吡格列酮与T2 DM发病机制相关的新作用模式，并表明靶向丙酮酸代谢可能导致开发有效的新T2 DM治疗方法。
Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2-14C]-pyruvate oxidation and pyruvate-driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose-dependently inhibited pyruvate-driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate-driven ATP synthesis, but did not alter pyruvate-driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies.
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影响因子：
3.5
作者：
Hectors, Tine L. M.;Vanparys, Caroline;Blust, Ronny
通讯作者：
Blust, Ronny
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
16.2
作者：
Eldor R;DeFronzo RA;Abdul-Ghani M
通讯作者：
Abdul-Ghani M
影响因子：
7.7
作者：
Daniele G;Eldor R;Merovci A;Clarke GD;Xiong J;Tripathy D;Taranova A;Abdul-Ghani M;DeFronzo RA
通讯作者：
DeFronzo RA
DOI：
10.1016/s1532-0456(03)00194-7
发表时间：
2003-09-01
影响因子：
3.9
作者：
Fujita, Y;Yamada, Y;Iga, T
通讯作者：
Iga, T