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Genes Nutr. 2019 Sep 9;14:27. doi: 10.1186/s12263-019-0647-5. eCollection 2019.

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

Author information

1
1Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.
2
2Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
3
3Department of Epidemiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
4
4Department of Toxicogenomics, GROW School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Abstract

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.

KEYWORDS:

Fatty acid oxidation; Glycolysis; Logical modelling; Metabolic flexibility; Metabolism; PDC; PDK; Regulation; Regulatory network

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

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