Impact of protein restriction on the regulation of cardiac carnitine palmitoyltransferase by malonyl-CoA.
Using a rat model of isocaloric protein restriction (8 v 20% protein diet), the study tested the hypothesis that growth retardation in utero, induced by maternal protein malnutrition, influences cardiac carnitine palmitoyltransferase (CPT) activity and regulation by malonyl-CoA in the newborn period, as well as in the offspring's adult life. The susceptibility of cardiac CPT to inhibition by malonyl-CoA was greater in adulthood than in hearts of 4-day-old neonatal rats, consistent with decreased expression of the L-CPT I isoform and increased expression of the M-CPT I isoform in adulthood. Maternal protein restriction during pregnancy resulted in reduced foetal growth and significantly (P < 0.05) lower rates of cardiac glucose utilization in vivo in the adult offspring, suggesting a switch to the use of substrates other than glucose. Maternal protein restriction did not affect CPT activity in hearts of 4-day-old neonatal offspring and, furthermore, the relative sensitivity of CPT activity to malonyl-CoA inhibition was unchanged by maternal protein restriction. It is therefore unlikely that maternal protein malnutrition has any major impact on cardiac mitochondrial fatty acid oxidation in the offspring during early postnatal development through altered regulatory characteristics of CPT. Transfer of rats previously maintained on 8% protein diet to 20% protein diet at weaning did not influence age-dependent changes in cardiac CPT activity or increase the susceptibility of cardiac CPT to inhibition by malonyl-CoA. Cardiac CPT activities and the susceptibility of cardiac CPT activities to malonyl-CoA inhibition in adulthood did not differ significantly between rats maintained on 8 or 20% protein throughout. Palmitate oxidation was suppressed to a similar extent by glucose in cardiac myocytes from adult rats maintained on 20% protein diet or 8% protein diet throughout and from rats transferred from 8 to 20% protein diet at weaning. The results exclude cardiac CPT activity as a direct target for the metabolic programming of cardiac function and cardiovascular disease associated with early growth retardation.
Department of Biochemistry, Faculty of Basic Medical Sciences, St Bartholomew's, UK.
M J
MJ
Holness
D A
DA
Priestman
M C
MC
Sugden
D000818:Animals; D000831:Animals, Newborn; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D010168:Palmitates; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose