Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway.
Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway.
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DOI：
10.1016/j.redox.2018.06.003
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Scott I
中科院分区：
文献类型：
--
作者：
Thapa D;Stoner MW;Zhang M;Xie B;Manning JR;Guimaraes D;Shiva S;Jurczak MJ;Scott I
线粒体提供心肌细胞收缩功能所需的约90%的ATP。虽然成年心肌细胞优先利用脂肪酸作为氧化磷酸化的燃料来源，但心肌线粒体在需要时可以转换为其他底物。这种变化部分是由细胞外和细胞内信号转导途径的组合驱动的，这些信号转导途径改变线粒体基因表达和酶活性。细胞外代谢信息传递到心肌线粒体的机制目前还没有很好的定义。最近的研究表明，adropin -一种肝脏分泌的肽激素-可以诱导骨骼肌线粒体燃料底物利用的变化，导致葡萄糖使用增加。在这项研究中，我们研究了Adropin是否可以调节心肌细胞线粒体葡萄糖利用途径。我们发现，刺激培养的心肌细胞与肾上腺素导致丙酮酸脱氢酶（PDH）的负调节PDK 4的表达减少，从而减少抑制PDH磷酸化。当H9 c2细胞中GPR 19（一种假定的Adropin受体）基因缺失时，Adropin对PDK 4表达的下调消失。单独GRP 19表达的丧失增加了PDK 4表达，导致线粒体呼吸减少。最后，我们表明，adropin介导的GPR 19信号依赖于p44/42 MAPK通路，这一途径的药理学破坏阻断adropin对心肌细胞中PDK 4的影响。这些研究结果表明，adropin可能是心脏燃料底物利用的关键调节因子，并暗示孤儿G蛋白偶联受体在控制线粒体燃料代谢的新信号通路中。
Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined. Recent work has shown that adropin – a liver-secreted peptide hormone – can induce changes in mitochondrial fuel substrate utilization in skeletal muscle, leading to increased glucose use. In this study, we examined whether adropin could regulate mitochondrial glucose utilization pathways in cardiac cells. We show that stimulation of cultured cardiac cells with adropin leads to decreased expression of the pyruvate dehydrogenase (PDH) negative regulator PDK4, which reduces inhibitory PDH phosphorylation. The downregulation of PDK4 expression by adropin is lost when GPR19 – a putative adropin receptor – is genetically depleted in H9c2 cells. Loss of GRP19 expression alone increased PDK4 expression, leading to a reduction in mitochondrial respiration. Finally, we show that adropin-mediated GPR19 signaling relies on the p44/42 MAPK pathway, and that pharmacological disruption of this pathway blocks the effects of adropin on PDK4 in cardiac cells. These findings suggest that adropin may be a key regulator of fuel substrate utilization in the heart, and implicates an orphan G-protein coupled receptor in a novel signaling pathway controlling mitochondrial fuel metabolism.
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影响因子：
29
作者：
Kumar KG;Trevaskis JL;Lam DD;Sutton GM;Koza RA;Chouljenko VN;Kousoulas KG;Rogers PM;Kesterson RA;Thearle M;Ferrante AW Jr;Mynatt RL;Burris TP;Dong JZ;Halem HA;Culler MD;Heisler LK;Stephens JM;Butler AA
通讯作者：
Butler AA
影响因子：
4.8
作者：
Scott, Iain;Webster, Bradley R.;Sack, Michael N.
通讯作者：
Sack, Michael N.
DOI：
10.1124/jpet.114.214700
发表时间：
2014-08-01
影响因子：
3.5
作者：
Garrett, Sara M.;Whitaker, Ryan M.;Schnellmann, Rick G.
通讯作者：
Schnellmann, Rick G.
影响因子：
7.7
作者：
Gao S;McMillan RP;Jacas J;Zhu Q;Li X;Kumar GK;Casals N;Hegardt FG;Robbins PD;Lopaschuk GD;Hulver MW;Butler AA
通讯作者：
Butler AA
脂肪素对具有胰岛素抵抗的饮食诱导的肥胖小鼠中葡萄糖耐受性和底物利用的治疗作用。
影响因子：
8.1
作者：
Gao S;McMillan RP;Zhu Q;Lopaschuk GD;Hulver MW;Butler AA
通讯作者：
Butler AA