Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin

Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2480-97. doi: 10.1152/ajpheart.01344.2005. Epub 2006 Jan 20.


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 (</=24 h) both dramatically induced cte1 and repressed acsl6 mRNA, with no significant effects on the other acsl isoforms. In contrast, high-fat feeding (4 wk) induced cte1 without affecting expression of the acsl isoforms in the heart. Investigation into the mechanism(s) responsible for these transcriptional changes uncovered roles for peroxisome proliferator-activated receptor-alpha (PPARalpha) and insulin as regulators of specific acsl isoforms and cte1 in the heart. Culturing ARCs with oleate (0.1-0.4 mM) or the PPARalpha agonists WY-14643 (1 muM) and fenofibrate (10 muM) consistently induced acsl1 and cte1. Conversely, PPARalpha null mouse hearts exhibited decreased acsl1 and cte1 expression. Culturing ARCs with insulin (10 nM) induced acsl6, whereas specific loss of insulin signaling within the heart (cardiac-specific insulin receptor knockout mice) caused decreased acsl6 expression. Our data expose differential regulation of acsl isoforms and cte1 in the heart, where acsl1 and cte1 are PPARalpha-regulated genes, whereas acsl6 is an insulin-regulated gene.

Publication types

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

MeSH terms

  • Animals
  • Circadian Rhythm
  • Coenzyme A Ligases / biosynthesis*
  • Coenzyme A Ligases / genetics
  • Cytosol / enzymology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diet
  • Dietary Fats / pharmacology
  • Fatty Acids / pharmacology*
  • Gene Expression Regulation, Enzymologic / physiology*
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacology*
  • In Vitro Techniques
  • Insulin / blood
  • Insulin / pharmacology*
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Myocardium / enzymology
  • Myocytes, Cardiac / drug effects
  • PPAR alpha / genetics
  • Palmitoyl-CoA Hydrolase / biosynthesis*
  • Palmitoyl-CoA Hydrolase / genetics
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction


  • Dietary Fats
  • Fatty Acids
  • Hypoglycemic Agents
  • Insulin
  • Isoenzymes
  • PPAR alpha
  • RNA
  • Palmitoyl-CoA Hydrolase
  • Coenzyme A Ligases