Title |
Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload
|
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Published in |
PLoS Computational Biology, August 2013
|
DOI | 10.1371/journal.pcbi.1003186 |
Pubmed ID | |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 3 | 43% |
Netherlands | 1 | 14% |
Canada | 1 | 14% |
Unknown | 2 | 29% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 3 | 43% |
Scientists | 2 | 29% |
Practitioners (doctors, other healthcare professionals) | 2 | 29% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 1 | <1% |
Malaysia | 1 | <1% |
Netherlands | 1 | <1% |
France | 1 | <1% |
Spain | 1 | <1% |
Unknown | 121 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 33 | 26% |
Researcher | 21 | 17% |
Student > Bachelor | 15 | 12% |
Student > Master | 9 | 7% |
Student > Postgraduate | 6 | 5% |
Other | 21 | 17% |
Unknown | 21 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 37 | 29% |
Biochemistry, Genetics and Molecular Biology | 32 | 25% |
Medicine and Dentistry | 6 | 5% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 3% |
Computer Science | 4 | 3% |
Other | 21 | 17% |
Unknown | 22 | 17% |