ACETYL-COA CARBOXYLASE INVOLVEMENT IN THE RAPID MATURATION OF FATTY-ACID OXIDATION IN THE NEWBORN RABBIT HEART

Fatty acid oxidation rapidly increases in the rabbit heart following birth. By inhibiting carnitine palmitoyltransferase 1 (CPT1), malonyl-CoA is a potent regulator of fatty acid oxidation in the heart. We therefore addressed the hypothesis that a decrease in acetyl-CoA carboxylase (ACC) activity and/or malonyl-CoA inhibition of CPT1 could account for the increase in the ability of the heart to oxidize fatty acids following birth. ACC activity and expression, malonyl-CoA levels, and mitochondrial CPT1 activity were measured in hearts from 1-day, 7-day, and 6-week-old rabbits. CPT1 activity and sensitivity to malonyl-CoA inhibition did not differ between 1-day, 7-day, or 6-week hearts (the IC50 for malonyl-CoA was 32.0 +/- 1.5, 36.0 +/- 0.3, and 36.3 nM respectively). Western blot analysis with streptavidin showed that all hearts expressed similar amounts of both a 265-kDa (ACC-265) and 280-kDa isoform (ACC-280) of ACC. A progressive and significant decrease in malonyl-CoA levels was seen in 1-day, 7-day, and g-week hearts (47 +/- 2, 40 +/- 2, and 26 +/- 2 nmol/g dry weight, respectively), paralleling a decline in ACC activity. We hypothesized that these developmental changes could be due to changes in hormonal regulation of cardiac ACC in the postnatal period. In isolated hearts from 1-day-old rabbits, the fatty acid oxidation rate was 9.01 +/- 1.10 nmol.g dry weight(-1).min(-1). Glucagon (1 ng/ml) did not alter this rate (11.03 +/- 1.42 nmol.g dry weight(-1).min(-1)), but insulin (100 microunits/ml) resulted in a significant decrease in rate. (4.81 +/- 0.82 nmol.g dry weight(-1).min(-1)). ACC activity was markedly elevated in 1-day-old hearts perfused with insulin compared to control hearts or glucagon perfused hearts (0.415 +/- 0.052, 0.095 +/- 0.018, and 0.133 +/- 0.013 nmol of malonyl-CoA produced.g dry weight(-1).min(-1), respectively). Malonyl-CoA levels were also markedly elevated in 1-day hearts perfused with insulin (123.0 +/- 8.3, 2.0 +/- 0.4, and 1.8 +/- 0.6 nmol/g dry weight in insulin, control, and glucagon hearts, respectively). In 7-day old rabbit hearts, the basal fatty acid oxidation rate had increased to 24.5 +/- 4.8 nmol.mg(-1). min(-1). In contrast to the 1-day-old hearts, insulin had no significant effect on fatty acid oxidation, although glucagon resulted in a significant increase in rates (38.9 +/- 12.2 and 80.7 +/- 9.1 nmol.g dry weight(-1) min(-1), respectively). Both ACC activity and malonyl-CoA levels were low in 7-day-old hearts and were also not dramatically altered by insulin or glucagon. Taken together these data suggest that the increase in fatty acid oxidation following birth is not due to a decreased sensitivity of CPT1 to malonyl-CoA inhibition, but rather to a decrease in malonyl-CoA production by ACC. The decrease in circulating insulin combined with the increase in glucagon seen in rabbits immediately following birth may result in a decrease in ACC activity and malonyl-CoA levels in the newborn heart. This may relieve the inhibition of CPT1 resulting in an increase in fatty acid oxidation. Low ACC activity and lack of sensitivity to insulin activation in 7-day-old hearts may ensure that fatty acid oxidation remains an important source of ATP production in the maturing heart.