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1 Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada
2 Department of Pediatrics, The University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed. E-mail: rodrigue{at}interchange.ubc.ca.
Glucocorticoid therapy is often associated with impaired insulin sensitivity and cardiovascular disease. The present study was designed to evaluate cardiac fatty acid composition and metabolism following acute dexamethasone (DEX) treatment. Using the euglycemic-hyperinsulinemic clamp, rats injected with DEX demonstrated a reduced glucose infusion rate. This whole-body insulin resistance was also associated with a heart specific increase in pyruvate dehydrogenase kinase 4 gene expression, and a reduction in the rate of glucose oxidation. DEX treatment increased basal and post-heparin plasma lipolytic activity. In the heart, palmitic and oleic acid levels were higher after 4h of DEX, and decreased to control levels within 8h. Measurement of polyunsaturated fatty acids demonstrated a drop in linoleic and gamma linolenic acid, with an increase in arachidonic acid after acute DEX injection. Tissue fatty acid (FA) can either be oxidized or stored as triglyceride (TG). At 4h, DEX augmented cardiac TG accumulation. However, this increase in tissue TG could not be maintained, such that at 8h following DEX, TG declined to control levels. AMP-activated protein kinase (AMPK) activation is known to promote FA oxidation through its control of acetyl-CoA carboxylase (ACC). Acute DEX promoted ACC phosphorylation, and increased cardiac palmitate oxidation, likely through its effects in increasing AMPK phosphorylation, and total AMPK protein and gene expression. Whether these acute effects of DEX on FA oxidation, TG storage, and arachidonic acid accumulation can be translated into increased cardiovascular risk following chronic therapy has yet to be determined.
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