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首页> 外文期刊>Cellular Physiology and Biochemistry >Troglitazone Regulates Anaplerosis via a Pull/Push Affect on Glutamate Dehydrogenase Mediated Glutamate Deamination in Kidney-derived Epithelial Cells; Implications for the Warburg Effect
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Troglitazone Regulates Anaplerosis via a Pull/Push Affect on Glutamate Dehydrogenase Mediated Glutamate Deamination in Kidney-derived Epithelial Cells; Implications for the Warburg Effect

机译：曲格列酮通过对肾脏来源的上皮细胞中的谷氨酸脱氢酶介导的谷氨酸脱氨作用的拉/推效应来调节动脉粥样硬化。沃堡效应的含义

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Mitochondrial Krebs cycle keto acid pool depends upon input from pyruvate and glutamate to maintain homeostasis. We studied the affect of glucose-derived pyruvate removal on compensatory input from glutamine-derived glutamate by accelerated glutamate metabolism via glutamate dehydrogenase (GDH). In glutamine minus glucose media (Gln-Glc), NHsub4/subsup+/sup production increased 41% without an increase in glutamine uptake consistent with accelerated glutamate metabolism via GDH. Alanine production dropped 40% consistent with a shift of glutamate from alanine aminotransferase (ALT) to GDH. Troglitazone (TRO) added to the Gln-Glc media further enhanced glutamate metabolism via GDH at the expense of glutamate metabolism via ALT since alanine production dropped an additional 70%. TRO reduced cell glutamate content 30% while increasing lactate production 5-fold consistent with blocking of cytosolic pyruvate formed from mitochondrial malate from reentering the cycle and maintaining keto acid pool homeostasis. Consequently mitochondrial keto acid pool deficit pulls glutamate via GDH into the cycle. Additionally TRO reduced cytosolic pH which effectively pushes glutamate via GDH, rather than merely shifting glutamate from ALT to GDH. Providing intramitochondrial pyruvate in the form of methyl pyruvate reduced glutamate metabolism via GDH and elevated glutamate metabolism via ALT to control levels restoring acid-base balance. Our findings are consistent with TRO regulation of anaplerosis dependent upon dual pull (cycle keto-acid deficit)/push (cytosolic acidosis) mechanisms.
机译：线粒体克雷布斯循环酮酸池依赖于丙酮酸和谷氨酸的输入来维持体内稳态。我们研究了通过谷氨酸脱氢酶（GDH）加速谷氨酸代谢，去除葡萄糖衍生的丙酮酸对谷氨酰胺衍生的谷氨酸补偿性输入的影响。在谷氨酰胺减葡萄糖培养基（Gln-Glc）中，NH 4 + 产量增加了41％，而谷氨酰胺的吸收却没有增加，这与谷氨酸通过GDH的代谢加速一致。谷氨酸产量下降40％，这与谷氨酸从谷氨酸转氨酶（ALT）转变为GDH一致。将曲格列酮（TRO）添加到Gln-Glc培养基中，可进一步通过GDH增强谷氨酸代谢，但以ALT为基础的谷氨酸代谢为代价，因为丙氨酸的产量再下降70％。 TRO将细胞谷氨酸含量降低了30％，同时将乳酸产量提高了5倍，这与阻止线粒体苹果酸形成的胞质丙酮酸重新进入循环并维持酮酸池体内稳态有关。因此，线粒体酮酸池缺乏会通过GDH将谷氨酸拉入循环。另外，TRO降低了细胞质的pH值，从而有效地通过GDH推动了谷氨酸，而不仅仅是将谷氨酸从ALT转移到GDH。以丙酮酸甲酯的形式提供线粒体内丙酮酸减少了通过GDH的谷氨酸代谢，并通过ALT升高了谷氨酸代谢，从而控制了恢复酸碱平衡的水平。我们的发现与依赖于双牵（循环酮酸缺乏）/推（胞质酸中毒）机制的动脉硬化的TRO调节一致。

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