Difference between revisions of "Van Eunen 2013 PLoS Comput Biol"
(Created page with "{{Publication |title=van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013) Biochemical competition m...") |
|||
| Line 11: | Line 11: | ||
|area=Respiration | |area=Respiration | ||
|diseases=Obesity | |diseases=Obesity | ||
|organism=Rat | |organism=Rat | ||
|tissues=Liver | |tissues=Liver | ||
| Line 19: | Line 18: | ||
|pathways=F, N | |pathways=F, N | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=Labels, | |additional=Labels, | ||
}} | }} | ||
Revision as of 16:48, 26 July 2017
| van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013) Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. PLoS Comput Biol 9:e1003186. |
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013) PLoS Comput Biol
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.
• O2k-Network Lab: NL Groningen Reijngoud RJ
Labels: MiParea: Respiration
Pathology: Obesity
Organism: Rat Tissue;cell: Liver Preparation: Isolated mitochondria
Regulation: Fatty acid Coupling state: OXPHOS Pathway: F, N HRR: Oxygraph-2k
Labels
