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

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.

• Authors: Karen van Eunen, Sereh M J Simons, Albert Gerding, Aycha Bleeker, Gijs den Besten, Catharina M L Touw, Sander M Houten, Bert K Groen, Klaas Krab, Dirk-Jan Reijngoud, Barbara M Bakker
• Journal: PLoS computational biology (PLoS Comput Biol) Vol. 9 Issue 8 Pg. e1003186 ( 2013) ISSN: 1553-7358 [Electronic] United States
• PMID: 23966849 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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