Low Activity of Mitochondrial HMG-CoA Synthase in Liver of Starved Piglets Is Due to Low Levels of Protein Despite High mRNA Levels

Barrero, María J.; Alho, Clarice Sampaio; Ortiz, J. A.; Hegardt, Fausto G.; Haro, Diego; Marrero, Pedro F.

doi:10.1006/abbi.2000.2146

Cited by 6 publications

(1 citation statement)

References 33 publications

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“…Besides the unique structure of porcine CPT I, the activity of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHMGCS), the key enzyme regulating ketogenesis, is extremely low in suckling piglets, which results in the reduced ketogenesis (8). The attenuated activity of mHMGCS appears not to be associated with a low mRNA abundance but rather a low rate of translation (5). The physiological significance of the unique structure of hepatic CPT I is not known, but it was suggested that fatty acid oxidation in mitochondria may be limited in neonatal pigs due to the diminished ketogenic pathway (8).…”

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Carnitine palmitoyltransferase I control of acetogenesis, the major pathway of fatty acid β-oxidation in liver of neonatal swine

Lin

Shim

Odle

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Lin X, Shim K, Odle J. Carnitine palmitoyltransferase I control of acetogenesis, the major pathway of fatty acid ␤-oxidation in liver of neonatal swine. Am J Physiol Regul Integr Comp Physiol 298: R1435-R1443, 2010. First published March 17, 2010 doi:10.1152/ajpregu.00634.2009.-To examine the regulation of hepatic acetogenesis in neonatal swine, carnitine palmitoyltransferase I (CPT I) activity was measured in the presence of varying palmitoyl-CoA (substrate) and malonyl-CoA (inhibitor) concentrations, and [1-14 C]-palmitate oxidation was simultaneously measured. Accumulation rates of 14 C-labeled acetate, ketone bodies, and citric acid cycle intermediates within the acid-soluble products were determined using radio-HPLC. Measurements were conducted in mitochondria isolated from newborn, 24-h (fed or fasted), and 5-mo-old pigs. Acetate rather than ketone bodies was the predominant radiolabeled product, and its production increased twofold with increasing fatty acid oxidation during the first 24-h suckling period. The rate of acetogenesis was directly proportional to CPT I activity. The high activity of CPT I in 24-h-suckling piglets was not attributable to an increase in CPT I gene expression, but rather to a large decrease in the sensitivity of CPT I to malonyl-CoA inhibition, which offset a developmental decrease in affinity of CPT I for palmitoyl-CoA. Specifically, the IC 50 for malonyl-CoA inhibition and Km value for palmitoyl-CoA measured in 24-h-suckling pigs were 1.8-and 2.7-fold higher than measured in newborn pigs. The addition of anaplerotic carbon from malate (10 mM) significantly reduced 14 C accumulation in acetate (P Ͻ 0.003); moreover, the reduction was much greater in newborn (80%) than in 24-h-fed (72%) and 5-mo-old pigs (55%). The results demonstrate that acetate is the primary product of hepatic mitochondrial ␤-oxidation in Sus scrofa and that regulation during early development is mediated primarily via kinetic modulation of CPT I. acetate; anaplerosis; carnitine palmitoyltransferase I activity; ketone bodies; mitochondria; Sus scrofa IT IS WELL ESTABLISHED THAT hepatic long-chain fatty acid oxidation is acutely controlled by a system in which carnitine palmitoyltransferase I (CPT I) is regulated allosterically by a change in malonyl-CoA concentration and/or the sensitivity to malonyl-CoA inhibition. This regulatory mechanism dictates fatty acid flux into mitochondria and controls the rates of ␤-oxidation and ketogenesis based on the animal's physiological status. The neonatal period represents a physiological state characterized by marked enhancement of fatty acid oxidation and ketogenesis. Both humans and rats present a significant hyperketonemia during the suckling period (40). Evidence confirms that the physiological hyperketonemia is a result of the high hepatic ketogenic rate in neonates consuming a diet (i.e., milk) that is high in fat and low in carbohydrate. In fact, more than 90% of the non-CO 2 carbon derived from fatty acid oxidation in liver homogenates is ketone bodies (21). Wh...

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