Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Jan;82(1 Pt 1):11–18. doi: 10.1016/S0006-3495(02)75369-1

Coupling of mitochondrial fatty acid uptake to oxidative flux in the intact heart.

J Michael O'Donnell 1, Nathaniel M Alpert 1, Lawrence T White 1, E Douglas Lewandowski 1
PMCID: PMC1302444  PMID: 11751291

Abstract

The coordination of long chain fatty acid (LCFA) transport across the mitochondrial membrane (V(PAL)) with subsequent oxidation rate through beta-oxidation and the tricarboxylic acid (TCA) cycle (V(tca)) has been difficult to characterize in the intact heart. Kinetic analysis of dynamic (13)C-NMR distinguished these flux rates in isolated rabbit hearts. Hearts were perfused in a 9.4 T magnet with either 0.5 mM [2,4,6,8,10,12,14,16-(13)C(8)] palmitate (n = 4), or 0.5 mM (13)C-labeled palmitate plus 0.08 mM unlabeled butyrate (n = 4). Butyrate is a short chain fatty acid (SCFA) that bypasses the LCFA transporters of mitochondria. In hearts oxidizing palmitate alone, the ratio of V(TCA) to V(PAL) was 8:1. This is consistent with one molecule of palmitate yielding eight molecules of acetyl-CoA for the subsequent oxidation through the TCA cycle. Addition of butyrate elevated this ratio; V(TCA)/V(PAL) = 12:1 due to an SCFA-induced increase in V(TCA) of 43% (p < 0.05). However, SCFA oxidation did not significantly reduce palmitate transport into the mitochondria: V(PAL) = 1.0 +/- 0.2 micromol/min/g dw with palmitate alone versus 0.9 +/- 0.1 with palmitate plus butyrate. Thus, the products of beta-oxidation are preferentially channeled to the TCA cycle, away from mitochondrial efflux via carnitine acetyltransferase.

Full Text

The Full Text of this article is available as a PDF (118.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abdel-aleem S., Nada M. A., Sayed-Ahmed M., Hendrickson S. C., St Louis J., Walthall H. P., Lowe J. E. Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes. J Mol Cell Cardiol. 1996 May;28(5):825–833. doi: 10.1006/jmcc.1996.0077. [DOI] [PubMed] [Google Scholar]
  2. Barger P. M., Kelly D. P. Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci. 1999 Jul;318(1):36–42. doi: 10.1097/00000441-199907000-00006. [DOI] [PubMed] [Google Scholar]
  3. Belke D. D., Larsen T. S., Lopaschuk G. D., Severson D. L. Glucose and fatty acid metabolism in the isolated working mouse heart. Am J Physiol. 1999 Oct;277(4 Pt 2):R1210–R1217. doi: 10.1152/ajpregu.1999.277.4.R1210. [DOI] [PubMed] [Google Scholar]
  4. Bowyer D. E., King J. P. Methods for the rapid separation and estimation of the major lipids of arteries and other tissues by thin-layer chromatography on small plates followed by microchemical assays. J Chromatogr. 1977 Sep 1;143(5):473–490. doi: 10.1016/s0378-4347(00)81794-6. [DOI] [PubMed] [Google Scholar]
  5. Brivet M., Boutron A., Slama A., Costa C., Thuillier L., Demaugre F., Rabier D., Saudubray J. M., Bonnefont J. P. Defects in activation and transport of fatty acids. J Inherit Metab Dis. 1999 Jun;22(4):428–441. doi: 10.1023/a:1005552106301. [DOI] [PubMed] [Google Scholar]
  6. Chance E. M., Seeholzer S. H., Kobayashi K., Williamson J. R. Mathematical analysis of isotope labeling in the citric acid cycle with applications to 13C NMR studies in perfused rat hearts. J Biol Chem. 1983 Nov 25;258(22):13785–13794. [PubMed] [Google Scholar]
  7. Crass M. F., 3rd, McCaskill E. S., Shipp J. C. Effect of pressure development on glucose and palmitate metabolism in perfused heart. Am J Physiol. 1969 Jun;216(6):1569–1576. doi: 10.1152/ajplegacy.1969.216.6.1569. [DOI] [PubMed] [Google Scholar]
  8. Goodwin G. W., Taegtmeyer H. Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation. Am J Physiol. 1999 Oct;277(4 Pt 1):E772–E777. doi: 10.1152/ajpendo.1999.277.4.E772. [DOI] [PubMed] [Google Scholar]
  9. Idell-Wenger J. A., Grotyohann L. W., Neely J. R. Coenzyme A and carnitine distribution in normal and ischemic hearts. J Biol Chem. 1978 Jun 25;253(12):4310–4318. [PubMed] [Google Scholar]
  10. Johnston D. L., Lewandowski E. D. Fatty acid metabolism and contractile function in the reperfused myocardium. Multinuclear NMR studies of isolated rabbit hearts. Circ Res. 1991 Mar;68(3):714–725. doi: 10.1161/01.res.68.3.714. [DOI] [PubMed] [Google Scholar]
  11. Kantor P. F., Dyck J. R., Lopaschuk G. D. Fatty acid oxidation in the reperfused ischemic heart. Am J Med Sci. 1999 Jul;318(1):3–14. doi: 10.1097/00000441-199907000-00002. [DOI] [PubMed] [Google Scholar]
  12. LaNoue K., Nicklas W. J., Williamson J. R. Control of citric acid cycle activity in rat heart mitochondria. J Biol Chem. 1970 Jan 10;245(1):102–111. [PubMed] [Google Scholar]
  13. Lewandowski E. D. Nuclear magnetic resonance evaluation of metabolic and respiratory support of work load in intact rabbit hearts. Circ Res. 1992 Mar;70(3):576–582. doi: 10.1161/01.res.70.3.576. [DOI] [PubMed] [Google Scholar]
  14. Lopaschuk G. D., Barr R. L. Measurements of fatty acid and carbohydrate metabolism in the isolated working rat heart. Mol Cell Biochem. 1997 Jul;172(1-2):137–147. [PubMed] [Google Scholar]
  15. Lopaschuk G. D., Belke D. D., Gamble J., Itoi T., Schönekess B. O. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994 Aug 4;1213(3):263–276. doi: 10.1016/0005-2760(94)00082-4. [DOI] [PubMed] [Google Scholar]
  16. Lopaschuk G. D., Hansen C. A., Neely J. R. Fatty acid metabolism in hearts containing elevated levels of CoA. Am J Physiol. 1986 Mar;250(3 Pt 2):H351–H359. doi: 10.1152/ajpheart.1986.250.3.H351. [DOI] [PubMed] [Google Scholar]
  17. Lopaschuk G. D., Spafford M. A., Davies N. J., Wall S. R. Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res. 1990 Feb;66(2):546–553. doi: 10.1161/01.res.66.2.546. [DOI] [PubMed] [Google Scholar]
  18. Lysiak W., Toth P. P., Suelter C. H., Bieber L. L. Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria. J Biol Chem. 1986 Oct 15;261(29):13698–13703. [PubMed] [Google Scholar]
  19. Malloy C. R., Sherry A. D., Jeffrey F. M. Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy. J Biol Chem. 1988 May 25;263(15):6964–6971. [PubMed] [Google Scholar]
  20. McGarry J. D., Brown N. F. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997 Feb 15;244(1):1–14. doi: 10.1111/j.1432-1033.1997.00001.x. [DOI] [PubMed] [Google Scholar]
  21. McGarry J. D., Woeltje K. F., Kuwajima M., Foster D. W. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev. 1989 May;5(3):271–284. doi: 10.1002/dmr.5610050305. [DOI] [PubMed] [Google Scholar]
  22. Neely J. R., Bowman R. H., Morgan H. E. Effects of ventricular pressure development and palmitate on glucose transport. Am J Physiol. 1969 Apr;216(4):804–811. doi: 10.1152/ajplegacy.1969.216.4.804. [DOI] [PubMed] [Google Scholar]
  23. Neely J. R., Liebermeister H., Battersby E. J., Morgan H. E. Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol. 1967 Apr;212(4):804–814. doi: 10.1152/ajplegacy.1967.212.4.804. [DOI] [PubMed] [Google Scholar]
  24. O'Donnell J. M., Doumen C., LaNoue K. F., White L. T., Yu X., Alpert N. M., Lewandowski E. D. Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts. Am J Physiol. 1998 Feb;274(2 Pt 2):H467–H476. doi: 10.1152/ajpheart.1998.274.2.H467. [DOI] [PubMed] [Google Scholar]
  25. Oram J. F., Bennetch S. L., Neely J. R. Regulation of fatty acid utilization in isolated perfused rat hearts. J Biol Chem. 1973 Aug 10;248(15):5299–5309. [PubMed] [Google Scholar]
  26. Randle P. J., England P. J., Denton R. M. Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J. 1970 May;117(4):677–695. doi: 10.1042/bj1170677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Robitaille P. M., Rath D. P., Abduljalil A. M., O'Donnell J. M., Jiang Z., Zhang H., Hamlin R. L. Dynamic 13C NMR analysis of oxidative metabolism in the in vivo canine myocardium. J Biol Chem. 1993 Dec 15;268(35):26296–26301. [PubMed] [Google Scholar]
  28. Saddik M., Gamble J., Witters L. A., Lopaschuk G. D. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem. 1993 Dec 5;268(34):25836–25845. [PubMed] [Google Scholar]
  29. Vanoverschelde J. L., Wijns W., Kolanowski J., Bol A., Decoster P. M., Michel C., Cogneau M., Heyndrickx G. R., Essamri B., Melin J. A. Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography. Am J Physiol. 1993 Mar;264(3 Pt 2):H701–H707. doi: 10.1152/ajpheart.1993.264.3.H701. [DOI] [PubMed] [Google Scholar]
  30. Weiss R. G., Gloth S. T., Kalil-Filho R., Chacko V. P., Stern M. D., Gerstenblith G. Indexing tricarboxylic acid cycle flux in intact hearts by carbon-13 nuclear magnetic resonance. Circ Res. 1992 Feb;70(2):392–408. doi: 10.1161/01.res.70.2.392. [DOI] [PubMed] [Google Scholar]
  31. Whitmer J. T., Idell-Wenger J. A., Rovetto M. J., Neely J. R. Control of fatty acid metabolism in ischemic and hypoxic hearts. J Biol Chem. 1978 Jun 25;253(12):4305–4309. [PubMed] [Google Scholar]
  32. Yu X., Alpert N. M., Lewandowski E. D. Modeling enrichment kinetics from dynamic 13C-NMR spectra: theoretical analysis and practical considerations. Am J Physiol. 1997 Jun;272(6 Pt 1):C2037–C2048. doi: 10.1152/ajpcell.1997.272.6.C2037. [DOI] [PubMed] [Google Scholar]
  33. Yu X., White L. T., Doumen C., Damico L. A., LaNoue K. F., Alpert N. M., Lewandowski E. D. Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts. Biophys J. 1995 Nov;69(5):2090–2102. doi: 10.1016/S0006-3495(95)80080-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. van der Vusse G. J., Glatz J. F., Stam H. C., Reneman R. S. Fatty acid homeostasis in the normoxic and ischemic heart. Physiol Rev. 1992 Oct;72(4):881–940. doi: 10.1152/physrev.1992.72.4.881. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES