Journal article
Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin
American journal of physiology. Heart and circulatory physiology, Vol.290(6), pp.H2480-2497
06/2006
DOI: 10.1152/ajpheart.01344.2005
PMID: 16428347
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 (</=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.
Details
- Title: Subtitle
- Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin
- Creators
- David J Durgan - USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Department of Pediatrics, 1100 Bates Street, Houston, TX 77030, USAJustin K SmithMargaret A HotzeOluwaseun EgbejimiKaralyn D CuthbertVlad G ZahaJason R B DyckE Dale AbelMartin E Young
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.290(6), pp.H2480-2497
- Publisher
- United States
- DOI
- 10.1152/ajpheart.01344.2005
- PMID
- 16428347
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Grant note
- HL 070070 / NHLBI NIH HHS HL 74259-01 / NHLBI NIH HHS R01 DK092065 / NIDDK NIH HHS
- Language
- English
- Date published
- 06/2006
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024545802771
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