Bistability in fatty-acid oxidation resulting from substrate inhibition

Fentaw Abegaz, Anne-Claire M F Martines, Marcel A Vieira-Lara, Melany Rios-Morales, Dirk-Jan Reijngoud, Ernst C Wit, Barbara M Bakker

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
34 Downloads (Pure)

Abstract

In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct stable and one unstable steady state could be attained with different fluxes. The two stable states were referred to as low-flux (disease) and high-flux (healthy) state. By a modular kinetic approach we traced the origin and causes of the bistability back to the distributive kinetics and the conservation of CoA, in particular in the last rounds of the β-oxidation. We then extended the model to investigate various interventions that may confer health benefits by activating the pathway, including (i) activation of the last enzyme MCKAT via its endogenous regulator p46-SHC protein, (ii) addition of a thioesterase (an acyl-CoA hydrolysing enzyme) as a safety valve, and (iii) concomitant activation of a number of upstream and downstream enzymes by short-chain fatty-acids (SCFA), metabolites that are produced from nutritional fibers in the gut. A high concentration of SCFAs, thioesterase activity, and inhibition of the p46Shc protein led to a disappearance of the bistability, leaving only the high-flux state. A better understanding of the switch behavior of the mitochondrial fatty-acid oxidation process between a low- and a high-flux state may lead to dietary and pharmacological intervention in the treatment or prevention of obesity and or non-alcoholic fatty-liver disease.

Original languageEnglish
Article numbere1009259
JournalPLoS Computational Biology
Volume17
Issue number8
DOIs
Publication statusPublished - Aug-2021

Cite this