Modulation of CPT‐1 activity and sensitivity by metoprolol

Abstract

Carnitine palmitoyltransferase-1 (CPT-1) activity is decreased by increasing malonyl CoA levels, increasing the sensitivity of CPT-1 to malonyl CoA, or decreasing catalytic activity. We have previously reported that chronic metoprolol treatment decreases both CPT-1 activity and sensitivity to malonyl CoA (MCoA). The aim of this study was to investigate the mechanism of this effect. We measured the expression of CPT-1, PPAR-α and pyruvate dehydrogenase kinase-4 (PDK-4) in control and diabetic hearts following chronic metoprolol treatment. To measure the acute effect of metoprolol on cardiac CPT-1, control and diabetic hearts were perfused for 30 minutes with metoprolol. CPT-1 activity and the IC50 of MCoA were measured. Metoprolol decreased total CPT-1 expression, but did not induce a CPT-1 isoform shift. PDK-4 expression did not correlate with CPT-1 expression, and PPAR-α expression was not altered by metoprolol. CPT-1 expression changes are therefore unlikely to be attributable to PPAR-α. Metoprolol acutely decreased both the activity and sensitivity of CPT-1. MCoA levels were decreased by metoprolol only in control hearts. MCoA levels did not correspond with fatty acid oxidation rates. These results indicate that metoprolol acutely regulates CPT-1 independent of the classical MCoA control mechanism. This work was supported by the Heart and Stroke Foundation of B.C. and Yukon.