Submitted to: Diabetes
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2006
Publication Date: 6/1/2006
Citation: Lockbridge, J.B., Durgan, D.J., Egbejimi, O., Stanley, W.C., Young, M.E. 2006. Differential influence of distinct fatty acids on cardiomyocyte metabolic gene expression. Diabetes. 55(Suppl.1):A442. Interpretive Summary:
Technical Abstract: Diabetes mellitus is a major risk factor for development of cardiovascular disease. Metabolic adaptation of the heart to increased fatty acids (FAs) in the diabetic milieu is mediated by induction of genes promoting FA oxidation (e.g. malonyl-CoA decarboxylase; mcd), as well as those suppressing carbohydrate oxidation (e.g., pyruvate dehydrogenase kinase 4; pdk4). In general, long chain saturated FAs have pathophysiological effects on the heart (e.g., apoptosis), while unsaturated FAs are cardioprotective, through mechanisms undefined at the molecular level. We hypothesized that FAs of varying chain length and saturation differentially regulate myocardial metabolic gene expression. Time- (6, 12, 24, and 48 hrs) and concentration- (0.1, 0.2, and 0.4 mM) dependent effects of octanoate (8:0), palmitate (16:0), stearate (18:0), oleate (18:1), and linoleic acid (18:2) on metabolic gene expression were investigated in isolated adult rat cardiomyocytes. Five known FA-responsive metabolic genes were studied; cytosolic thioesterase 1 (cte1), mitochondrial thioesterase 1 (mte1), mcd, pdk4, and uncoupling protein 3 (ucp3). Octanoate consistently induced metabolic genes to the lowest extent. Increasing saturated FA carbon chain length from 16 (palmitate) to 18 (stearate) consistently reduced induction of metabolic genes. Incorporation of one double bond (i.e. stearate versus oleate) consistently increased induction of metabolic genes. Response of metabolic genes to FAs exhibited one of two patterns: 1) cte1 and mte1 were induced by all FAs, with the greatest response to palmitate; and 2) mcd, pdk4, and ucp3 were not induced by octanoate, and were induced by oleate to the greatest extent. These observations suggest fatty acids influence myocardial metabolic gene expression through at least two distinct mechanisms, and may partially explain why unsaturated FAs are cardioprotective, while saturated are detrimental.