Acetyl-CoA carboxylase involvement in the rapid maturation of fatty acid oxidation in the newborn rabbit heart

• Published in: The Journal of biological chemistry Vol. 269; no. 41; pp. 25871 - 25878
• Main Authors: Lopaschuk, G D, Witters, L A, Itoi, T, Barr, R, Barr, A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-10-1994; American Society for Biochemistry and Molecular Biology
• Subjects: Acetyl Coenzyme A - analysis; Acetyl-CoA Carboxylase - metabolism; Age Factors; Animals; Animals, Newborn; Carnitine O-Palmitoyltransferase - drug effects; Carnitine O-Palmitoyltransferase - metabolism; Citrates - metabolism; Dose-Response Relationship, Drug; Fatty Acids - metabolism; Glucagon - pharmacology; Heart - growth & development; Insulin - pharmacology; Malonyl Coenzyme A - analysis; Malonyl Coenzyme A - pharmacology; Mitochondria, Heart - enzymology; Myocardium - enzymology; Myocardium - metabolism; Oxidation-Reduction; Palmitates - metabolism; Perfusion; Rabbits
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)47327-9

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 6-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).