Accumulation of long-chain acylcarnitine and 3-hydroxy acylcarnitine molecular species in diabetic myocardium: Identification of alterations in mitochondrial fatty acid processing in diabetic myocardium by shotgun lipidomics

Xiong Su, Xianlin Han, David J. Mancuso, Dana R. Abendschein, Richard W. Gross

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Diabetic cardiomyopathy is the result of maladaptive changes in energy homeostasis. However, the biochemical mechanisms underlying dysfunctional lipid metabolism in diabetic myocardium are incompletely understood. Herein, we exploit shotgun lipidomics to demonstrate a 4-fold increase in acylcarnitines in diabetic myocardium, which was reversible upon insulin treatment. Analysis of acylcarnitine molecular species in myocardium unexpectedly identified acylcarnitine molecular species containing a mass shift of 16 amu in comparison to the anticipated molecular species. Synthesis of 3-hydroxy acylcarnitine identified the natural products as the 3-hydroxylated acylcarnitines through comparisons of diagnostic fragmentation patterns of synthetic and naturally occurring constituents using tandem mass spectrometry. Diabetes induced an increase of both calcium-independent phospholipase A2 (iPLA 2) mRNA and iPLA2 activity in rat myocardium. Cardiac ischemia in myocardium genetically engineered to overexpress iPLA2 dramatically increased the amount of acylcarnitine present in myocardium. Moreover, mechanism-based inactivation of iPLA2 in either wild-type or transgenic myocardium ablated a substantial portion of the acylcarnitine increase. Collectively, these results identify discrete insulin remediable abnormalities in mitochondrial fatty acid processing in diabetic myocardium and identify iPLA2 as an important enzymatic contributor to the pool of fatty acids that can be used for acylcarnitine synthesis and energy production in myocardium.

Original languageEnglish
Pages (from-to)5234-5245
Number of pages12
JournalBiochemistry
Volume44
Issue number13
DOIs
StatePublished - Apr 5 2005

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