Coenzyme A–mediated degradation of pyruvate dehydrogenase kinase 4 promotes cardiac metabolic flexibility after high-fat feeding in mice

Christopher Schafer, Zachary T. Young, Catherine A. Makarewich, Abdallah Elnwasany, Caroline Kinter, Michael Kinter, Luke I. Szweda

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4 Scopus citations

Abstract

Cardiac energy is produced primarily by oxidation of fatty acids and glucose, with the relative contributions of each nutrient being sensitive to changes in substrate availability and energetic demand. A major contributor to cardiac metabolic flexibility is pyruvate dehydrogenase (PDH), which converts glucose-derived pyruvate to acetyl-CoA within the mitochondria. PDH is inhibited by phosphorylation dependent on the competing activities of pyruvate dehydrogenase kinases (PDK1– 4) and phosphatases (PDP1–2). A single high-fat meal increases cardiac PDK4 content and subsequently inhibits PDH activity, reducing pyruvate utilization when abundant fatty acids are available. In this study, we demonstrate that diet-induced increases in PDK4 are reversible and characterize a novel pathway that regulates PDK4 degradation in response to the cardiac metabolic environment. We found that PDK4 degradation is promoted by CoA (CoASH), the levels of which declined in mice fed a high-fat diet and normalized following transition to a control diet. We conclude that CoASH functions as a metabolic sensor linking the rate of PDK4 degradation to fatty acid availability in the heart. However, prolonged high-fat feeding followed by return to a low-fat diet resulted in persistent in vitro sensitivity of PDH to fatty acid–induced inhibition despite reductions in PDK4 content. Moreover, increases in the levels of proteins responsible for -oxidation and rates of palmitate oxidation by isolated cardiac mitochondria following long-term consumption of high dietary fat persisted after transition to the control diet. We propose that these changes prime PDH for inhibition upon reintroduction of fatty acids.

Original languageEnglish (US)
Pages (from-to)6915-6924
Number of pages10
JournalJournal of Biological Chemistry
Volume293
Issue number18
DOIs
Publication statusPublished - Jan 1 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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