vanEunen6

Title

Biochemical Competition Makes Fatty-Acid b-Oxidation Vulnerable to Substrate Overload

Authors

Karen van Eunen1,2, Sereh M. J. Simons1, Albert Gerding1,3, Aycha Bleeker1, Gijs den Besten1,2, Catharina M. L. Touw1, Sander M. Houten4, Bert K. Groen1,2, Klaas Krab5, Dirk-Jan Reijngoud1,2,3, Barbara M. Bakker1,2

Affiliations

11 Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2 Netherlands Consortium for Systems Biology, Amsterdam, The Netherlands, 3 Department of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 4 Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children?s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 5 Department of Molecular Cell Physiology, Netherlands Institute for Systems Biology, VU University Amsterdam, Amsterdam, The Netherlands

Abstract

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

Journal

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

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