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。

IF 3.3 3区 医学 Q2 GENETICS & HEREDITY
Genes and Nutrition Pub Date : 2019-09-09 eCollection Date: 2019-01-01 DOI:10.1186/s12263-019-0647-5
Samar Hk Tareen, Martina Kutmon, Ilja Cw Arts, Theo M de Kok, Chris T Evelo, Michiel E Adriaens
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引用次数: 8

摘要

背景:代谢灵活性是指生物体在不同底物之间进行能量代谢的能力,以应对生物体不断变化的营养状态和需求。在细胞水平上,代谢灵活性围绕着三羧酸循环,通过将乙酰辅酶A的产生从葡萄糖转换为脂肪酸,反之亦然。在这项研究中,我们通过构建一个连接糖酵解、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该模型的行为。结果:我们观察到底物转换通常通过丙酮酸脱氢酶激酶(PDK)对丙酮酸脱氢酶复合物(PDC)的抑制而发生,丙酮酸脱氢酶激酶将代谢从糖酵解转移到脂肪酸氧化。此外,我们能够验证PDK的四个不同调控模型,以包含已知的生物学观察结果,从而得出所有四个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,细胞代谢的灵活性取决于PDC-PDK的调节相互作用,PDC-PCK是改变代谢底物的关键调节开关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level.

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level.

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level.

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level.

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.

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来源期刊
Genes and Nutrition
Genes and Nutrition 生物-遗传学
CiteScore
6.60
自引率
0.00%
发文量
14
审稿时长
6-12 weeks
期刊介绍: This journal examines the relationship between genetics and nutrition, with the ultimate goal of improving human health. It publishes original research articles and review articles on preclinical research data coming largely from animal, cell culture and other experimental models as well as critical evaluations of human experimental data to help deliver products with medically proven use.
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