Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2006
Publication Date: 6/1/2006
Citation: Durgan, D.J., Smith, J.K., Hotze, M.A., Egbejimi, O., Cuthbert, K.D., Zaha, V.G., Dyck, J.R.B., Abel, E.D., Young, M.E. 2006. 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. 290(6):H2480-H2497. Interpretive Summary: Fatty acids (a component of fat) are an important fuel source for the heart. However, if the levels of fatty acids entering the cells of the heart are in excess of the requirements for contraction, then those fatty acids can have detrimental effects on the heart and its ability to function normally. This becomes important in humans with conditions such as obesity and diabetes. It is unclear whether fatty acids can be channeled into beneficial versus detrimental pathways. The present study investigated a family of proteins in the heart that potentially allow such channeling to occur. The results show that members of this family of proteins are regulated by different mechanisms, supporting the idea that activation of a specific member during a disease state may channel fatty acids into detrimental pathways.
Technical 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 (PPAR-alpha) and insulin as regulators of specific acsl isoforms and cte1 in the heart. Culturing ARCs with oleate (0.1–0.4 mM) or the PPAR-alpha agonists WY-14643 (1 µM) and fenofibrate (10 µM) consistently induced acsl1 and cte1. Conversely, PPAR-alpha 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 PPAR-alpha regulated genes, whereas acsl6 is an insulin-regulated gene.