Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine

Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E622-E633. doi: 10.1152/ajpendo.00081.2018. Epub 2018 Jul 17.

Abstract

High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C3 and C4) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C3 and C4 dicarboxylylcarnitines, in cardiac conditions such as heart failure.

Keywords: cardiac metabolism; dicarboxylyl-CoA; dicarboxylylcarnitine; propionate; stable isotope analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Acyl Coenzyme A / metabolism
  • Animals
  • Carnitine / pharmacology*
  • Citric Acid Cycle / drug effects
  • Citric Acid Cycle / physiology
  • Coenzyme A / metabolism*
  • Energy Metabolism / drug effects*
  • Energy Metabolism / physiology
  • Fatty Acids / metabolism
  • Glucose / metabolism
  • Heart / drug effects*
  • Isolated Heart Preparation
  • Liver / metabolism
  • Malates / metabolism
  • Male
  • Metabolic Flux Analysis
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Myocardium / metabolism*
  • Oxidation-Reduction / drug effects
  • Propionates / metabolism*
  • Pyruvic Acid / metabolism
  • Rats

Substances

  • Acyl Coenzyme A
  • Fatty Acids
  • Malates
  • Propionates
  • methylmalonyl-coenzyme A
  • propionyl-coenzyme A
  • Acetyl Coenzyme A
  • malic acid
  • Pyruvic Acid
  • Glucose
  • propionic acid
  • Carnitine
  • Coenzyme A