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.

Original languageEnglish
Article number27
Number of pages16
JournalGenes and nutrition
Volume14
Issue number1
DOIs
Publication statusPublished - 9 Sep 2019

Keywords

  • CANCER
  • CELLS
  • DEHYDROGENASE
  • DICHLOROACETATE INDUCES APOPTOSIS
  • EXPRESSION
  • Fatty acid oxidation
  • Glycolysis
  • KINASE
  • Logical modelling
  • MITOCHONDRIA
  • Metabolic flexibility
  • Metabolism
  • NETWORKS
  • PDC
  • PDK
  • RESISTANCE
  • Regulation
  • Regulatory network

Cite this

@article{1de018cfda7f467da414f59429da34da,
title = "Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level",
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 = "CANCER, CELLS, DEHYDROGENASE, DICHLOROACETATE INDUCES APOPTOSIS, EXPRESSION, Fatty acid oxidation, Glycolysis, KINASE, Logical modelling, MITOCHONDRIA, Metabolic flexibility, Metabolism, NETWORKS, PDC, PDK, RESISTANCE, Regulation, Regulatory network",
author = "Tareen, {Samar Hk} and Martina Kutmon and Arts, {Ilja Cw} and {de Kok}, {Theo M} and Evelo, {Chris T} and Adriaens, {Michiel E}",
year = "2019",
month = "9",
day = "9",
doi = "10.1186/s12263-019-0647-5",
language = "English",
volume = "14",
journal = "Genes and nutrition",
issn = "1555-8932",
publisher = "BioMed Central Ltd",
number = "1",

}

TY - JOUR

T1 - Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level

AU - Tareen, Samar Hk

AU - Kutmon, Martina

AU - Arts, Ilja Cw

AU - de Kok, Theo M

AU - Evelo, Chris T

AU - Adriaens, Michiel E

PY - 2019/9/9

Y1 - 2019/9/9

N2 - 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.

AB - 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.

KW - CANCER

KW - CELLS

KW - DEHYDROGENASE

KW - DICHLOROACETATE INDUCES APOPTOSIS

KW - EXPRESSION

KW - Fatty acid oxidation

KW - Glycolysis

KW - KINASE

KW - Logical modelling

KW - MITOCHONDRIA

KW - Metabolic flexibility

KW - Metabolism

KW - NETWORKS

KW - PDC

KW - PDK

KW - RESISTANCE

KW - Regulation

KW - Regulatory network

U2 - 10.1186/s12263-019-0647-5

DO - 10.1186/s12263-019-0647-5

M3 - Article

C2 - 31516637

VL - 14

JO - Genes and nutrition

JF - Genes and nutrition

SN - 1555-8932

IS - 1

M1 - 27

ER -