ABSTRACT
The molecular mechanism(s) responsible for channeling long-chain fatty acids (LCFAs) into oxidative versus nonoxidative pathways is (are) poorly understood in the heart. Intracellular LCFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoAs) by a family of long-chain acyl-CoA synthetases (ACSLs). Cytosolic thioesterase 1 (CTE1) hydrolyzes cytosolic LCFA-CoAs to LCFAs, generating a potential futile cycle at the expense of ATP utilization. We hypothesized that ACSL isoforms and CTE1 are differentially regulated in the heart during physiological and pathophysiological conditions. Using quantitative RT-PCR, we report that the five known acsl isoforms (acsl1, acsl3, acsl4, acsl5, and acsl6) and cte1 are expressed in whole rat and mouse hearts, as well as adult rat cardiomyocytes (ARCs). Streptozotocin-induced insulin-dependent diabetes (4 wk) and fasting (
Subject(s)
Coenzyme A Ligases/biosynthesis , Cytosol/enzymology , Fatty Acids/pharmacology , Gene Expression Regulation, Enzymologic/physiology , Hypoglycemic Agents/pharmacology , Insulin/pharmacology , Palmitoyl-CoA Hydrolase/biosynthesis , Animals , Circadian Rhythm , Coenzyme A Ligases/genetics , Diabetes Mellitus, Experimental/metabolism , Diet , Dietary Fats/pharmacology , Hypoglycemic Agents/blood , In Vitro Techniques , Insulin/blood , Isoenzymes/biosynthesis , Isoenzymes/genetics , Male , Mice , Mice, Knockout , Myocardium/enzymology , Myocytes, Cardiac/drug effects , PPAR alpha/genetics , Palmitoyl-CoA Hydrolase/genetics , RNA/biosynthesis , RNA/isolation & purification , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The energy demands of the heart are normally met by oxidation of both glucose and fatty acids. Fatty acid oxidation is limited by the uptake of fatty acyl coenzyme A (CoA) into the mitochondria, a process regulated by carnitine palmitoyltransferase (CPT)1. Malonyl CoA is a potent endogenous inhibitor of CPT1, and therefore plays an integral role in the control of myocardial fatty acid oxidation. Malonyl-CoA decarboxylase (MCD) is responsible for the removal of malonyl CoA and may control myocardial fatty acid oxidation. Indeed, strategies using MCD inhibitors and MCD knockout mice have provided the first evidence for a direct role of MCD in the control of myocardial fatty acid oxidation. Based on these studies, pharmacologic inhibition of MCD has been proposed to be a viable approach for the treatment of ischemic heart disease resulting from a variety of pathologic conditions, including coronary artery diseases, pathologic hypertrophy, and hypertension.