title: Acetyl-CoA carboxylase involvement in the rapid maturation of fatty acid oxidation in the newborn rabbit heart.
abstract: 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).(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada.
authors.forename: G D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: L A
authors.initials: LA
authors.lastname: Witters
authors.forename: T
authors.initials: T
authors.lastname: Itoi
authors.forename: R
authors.initials: R
authors.lastname: Barr
authors.forename: A
authors.initials: A
authors.lastname: Barr
mesh_terms: D000105:Acetyl Coenzyme A / Q000032:analysis; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects / Q000378:metabolism*; D002951:Citrates / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D005934:Glucagon / Q000494:pharmacology; D006321:Heart / Q000254:growth & development*; D007328:Insulin / Q000494:pharmacology; D008316:Malonyl Coenzyme A / Q000032:analysis / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D010477:Perfusion; D011817:Rabbits
chemical_list: D002951:Citrates; D005227:Fatty Acids; D007328:Insulin; D010168:Palmitates; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D005934:Glucagon; D002334:Carnitine O-Palmitoyltransferase; D000103:Acetyl-CoA Carboxylase