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Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level.
Genes and Nutrition ( IF 3.3 ) Pub Date : 2019-09-09 , DOI: 10.1186/s12263-019-0647-5
Samar Hk Tareen 1 , Martina Kutmon 1, 2 , Ilja Cw Arts 1, 3 , Theo M de Kok 1, 4 , Chris T Evelo 1, 2 , Michiel E Adriaens 1
Affiliation  

Background Metabolic flexibility is the ability of an organism to switch between substrates for energy metabolism, in response to the changing nutritional state and needs of the organism. On the cellular level, metabolic flexibility revolves around the tricarboxylic acid cycle by switching acetyl coenzyme A production from glucose to fatty acids and vice versa. In this study, we modelled cellular metabolic flexibility by constructing a logical model connecting glycolysis, fatty acid oxidation, fatty acid synthesis and the tricarboxylic acid cycle, and then using network analysis to study the behaviours of the model. Results We observed that the substrate switching usually occurs through the inhibition of pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinases (PDK), which moves the metabolism from glycolysis to fatty acid oxidation. Furthermore, we were able to verify four different regulatory models of PDK to contain known biological observations, leading to the biological plausibility of all four models across different cells and conditions. Conclusion These results suggest that the cellular metabolic flexibility depends upon the PDC-PDK regulatory interaction as a key regulatory switch for changing metabolic substrates.

中文翻译:

逻辑模型揭示了 PDC-PDK 相互作用作为细胞水平上驱动代谢灵活性的调节开关。

背景代谢灵活性是生物体响应不断变化的营养状态和生物体需求而在能量代谢底物之间切换的能力。在细胞水平上,代谢灵活性围绕三羧酸循环,通过将乙酰辅酶 A 的生产从葡萄糖转换为脂肪酸,反之亦然。在本研究中,我们通过构建连接糖酵解、脂肪酸氧化、脂肪酸合成和三羧酸循环的逻辑模型来模拟细胞代谢灵活性,然后使用网络分析来研究模型的行为。结果我们观察到底物转换通常通过丙酮酸脱氢酶激酶(PDK)抑制丙酮酸脱氢酶复合物(PDC)而发生,从而将代谢从糖酵解转移到脂肪酸氧化。此外,我们能够验证 PDK 的四种不同调控模型以包含已知的生物学观察结果,从而得出所有四种模型在不同细胞和条件下的生物学合理性。结论 这些结果表明细胞代谢灵活性取决于 PDC-PDK 调节相互作用,作为改变代谢底物的关键调节开关。
更新日期:2020-04-22
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