Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload

PLoS Comput Biol. 2013;9(8):e1003186. doi: 10.1371/journal.pcbi.1003186. Epub 2013 Aug 15.

Abstract

Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Fatty Acids / metabolism*
  • Female
  • Kinetics
  • Liver / enzymology
  • Liver / metabolism
  • Metabolic Networks and Pathways / physiology*
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Models, Biological*
  • NAD / metabolism
  • Obesity / metabolism
  • Oxidation-Reduction
  • Palmitoyl Coenzyme A / metabolism
  • Palmitoylcarnitine / metabolism
  • Rats
  • Rats, Wistar
  • Reproducibility of Results

Substances

  • Fatty Acids
  • acylcarnitine
  • NAD
  • Palmitoyl Coenzyme A
  • Palmitoylcarnitine
  • Carnitine

Grant support

This work was funded by the Netherlands Genomics Initiative via the Netherlands Centre for Systems Biology, a Rosalind Franklin Fellowship from the University of Groningen to BMB and an NWO grant (Centers for Systems Biology Research) to BMB, DJR and AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.