Biochemical Competition Makes Fatty-Acid beta -Oxidation Vulnerable to Substrate Overload: e1003186

• Published in: PLoS computational biology Vol. 9; no. 8
• Main Authors: Eunen, Karen van, Simons, Sereh MJ, Gerding, Albert, Bleeker, Aycha, Besten, Gijs den, Touw, Catharina ML, Houten, Sander M, Groen, Bert K, Krab, Klaas, Reijngoud, Dirk-Jan
• Format: Journal Article
• Language: English
• Published: 01.08.2013
• ISSN: 1553-7358
• DOI: 10.1371/journal.pcbi.1003186

Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid beta -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 beta -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 beta -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 beta -oxidation and mitochondrial respiration.