title: 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: Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Karen
authors: K
authors: van Eunen
authors: Sereh M J
authors: SM
authors: Simons
authors: Albert
authors: A
authors: Gerding
authors: Aycha
authors: A
authors: Bleeker
authors: Gijs
authors: G
authors: den Besten
authors: Catharina M L
authors: CM
authors: Touw
authors: Sander M
authors: SM
authors: Houten
authors: Bert K
authors: BK
authors: Groen
authors: Klaas
authors: K
authors: Krab
authors: Dirk-Jan
authors: DJ
authors: Reijngoud
authors: Barbara M
authors: BM
authors: Bakker
mesh_terms: D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results
chemical_list: D005227:Fatty Acids; C116917:acylcarnitine; D009243:NAD; D010171:Palmitoyl Coenzyme A; D010172:Palmitoylcarnitine; D002331:Carnitine
references: Biochim Biophys Acta. 1991 Jan 28;1081(2):121-8
references: 1998730
references: Biochim Biophys Acta. 2010 Jan;1801(1):1-22
references: 19782765
references: Diabetologia. 2012 Jul;55(7):2044-53
references: 22532389
references: Biochim Biophys Acta. 2009 Aug;1791(8):806-15
references: 19465148
references: Exp Physiol. 2010 Feb;95(2):380-97
references: 19801387
references: FASEB J. 1999 Nov;13(14):2051-60
references: 10544188
references: J Biol Chem. 1984 Jul 25;259(14):8748-52
references: 6378901
references: J Biol Chem. 1989 Oct 5;264(28):16483-8
references: 2506178
references: J Biol Chem. 2009 Aug 21;284(34):22840-52
references: 19553674
references: Obesity (Silver Spring). 2010 Sep;18(9):1695-700
references: 20111019
references: Mol Biosyst. 2012 Oct;8(10):2545-58
references: 22699794
references: Biochem Soc Trans. 2001 May;29(Pt 2):279-82
references: 11356167
references: Toxicol Sci. 2002 Feb;65(2):220-7
references: 11812926
references: J Biol Chem. 1995 Jan 13;270(2):530-5
references: 7822275
references: J Cell Physiol. 2008 Nov;217(2):478-85
references: 18561258
references: Eur J Biochem. 2004 Jul;271(14):2905-22
references: 15233787
references: J Inherit Metab Dis. 2010 Oct;33(5):467-8
references: 20842433
references: J Biochem. 1981 Aug;90(2):511-9
references: 6117552
references: Biochim Biophys Acta. 1999 Mar 25;1437(3):402-8
references: 10101273
references: J Biochem. 1980 Oct;88(4):1059-70
references: 6778855
references: J Biol Chem. 1992 Jan 15;267(2):1034-41
references: 1730633
references: EMBO J. 2004 Jul 21;23(14):2745-54
references: 15229654
references: J Biol Chem. 1992 Jan 15;267(2):1027-33
references: 1730632
references: J Cell Biochem. 2006 Oct 15;99(3):860-7
references: 16721829
references: Diabetes. 2009 Nov;58(11):2429-43
references: 19875619
references: J Inherit Metab Dis. 2008 Feb;31(1):88-96
references: 18188679
references: Clin Chem. 1978 Oct;24(10):1663-73
references: 359193
references: J Biol Chem. 1985 Jan 25;260(2):1311-25
references: 3968063
references: Cell Metab. 2008 Jan;7(1):45-56
references: 18177724
references: Endocrinol Metab Clin North Am. 2008 Sep;37(3):635-46, viii-ix
references: 18775356
references: Arch Biochem Biophys. 1980 Aug;203(1):372-83
references: 6773478
references: J Biol Chem. 1984 Dec 25;259(24):15040-5
references: 6439716
references: Diabetes. 2006 Aug;55(8):2277-85
references: 16873691
references: Eur J Nutr. 2012 Feb;51(1):1-18
references: 22134503
references: Ann Biomed Eng. 2002 Jun;30(6):808-27
references: 12220081
references: Ann Biomed Eng. 1983;11(5):361-84
references: 6592996
references: J Inherit Metab Dis. 2010 Oct;33(5):555-61
references: 20830526
references: Biochem Soc Trans. 2000 Feb;28(2):177-82
references: 10816122
references: Biochim Biophys Acta. 2010 Mar;1801(3):235-9
references: 19944187
references: J Biol Chem. 1983 Jan 25;258(2):1066-76
references: 6401712
references: Bioorg Med Chem. 2011 May 15;19(10):3039-53
references: 21515056
references: J Inherit Metab Dis. 2008 Oct;31(5):619-29
references: 18836848
references: J Biochem. 1996 Apr;119(4):775-82
references: 8743581
references: Biochem J. 1973 Apr;132(4):717-30
references: 4721607
references: J Biol Chem. 2007 Aug 24;282(34):24525-37
references: 17591785
references: BMC Syst Biol. 2009 Jan 06;3:2
references: 19126203
references: Am J Physiol. 1994 Jul;267(1 Pt 1):E95-101
references: 8048519