Tissue-specific short chain fatty acid metabolism and slow metabolic recovery after ischemia from hyperpolarized NMR in vivo

Research output: Contribution to journalArticle

Abstract

Mechanistic details of mammalian metabolism in vivo and dynamic metabolic changes in intact organisms are difficult to monitor because of the lack of spatial, chemical, or temporal resolution when applying traditional analytical tools. These limitations can be addressed by sensitivity enhancement technology for fast in vivo NMR assays of enzymatic fluxes in tissues of interest. We apply this methodology to characterize organ-specific short chain fatty acid metabolism and the changes of carnitine and coenzyme A pools in ischemia reperfusion. This is achieved by assaying acetyl-CoA synthetase and acetyl-carnitine transferase catalyzed transformations in vivo. The fast and predominant flux of acetate and propionate signal into acyl-carnitine pools shows the efficient buffering of free CoA levels. Sizeable acetyl-carnitine formation from exogenous acetate is even found in liver, where acetyl-CoA synthetase and acetyl-carnitine transferase activities have been assumed sequestered in different compartments. In vivo assays of altered acetate metabolism were applied to characterize pathological changes of acetate metabolism upon ischemia. Coenzyme pools in ischemic skeletal muscle are reduced in vivo even 1 h after disturbing muscle perfusion. Impaired mitochondrial metabolism and slow restoration of free CoA are corroborated by assays employing fumarate to show persistently reduced tricarboxylic acid (TCA) cycle activity upon ischemia. In the same animal model, anaerobic metabolism of pyruvate and tissue perfusion normalize faster than mitochondrial bioenergetics.

Details

Authors
  • Pernille R Jensen
  • Torben Peitersen
  • Magnus Karlsson
  • René In 't Zandt
  • Anna Gisselsson
  • Georg Hansson
  • Sebastian Meier
  • Mathilde H Lerche
External organisations
  • Imagnia AB, Malmö
  • Carlsberg Research Center / Carlsberg Laboratory
Research areas and keywords

Keywords

  • Acetylcarnitine, Animals, Carnitine, Citric Acid Cycle, Coenzyme A, Coenzyme A Ligases, Energy Metabolism, Fatty Acids, Fumarates, Liver, Mice, Mitochondria, Liver, Mitochondria, Muscle, Muscle, Skeletal, Organ Specificity, Reperfusion Injury, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)36077-82
Number of pages6
JournalJournal of Biological Chemistry
Volume284
Issue number52
Publication statusPublished - 2009 Dec 25
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes