Hepatic ketogenesis in newborn pigs is limited by low mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity.
In newborn-pig hepatocytes, the rate of oleate oxidation is extremely low, despite a very low malonyl-CoA concentration. By contrast, the sensitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inhibition is high, as suggested by the very low concentration of malonyl-CoA required for 50% inhibition of CPT I (IC50). The rates of oleate oxidation and ketogenesis are respectively 70 and 80% lower in mitochondria isolated from newborn-pig liver than from starved-adult-rat liver mitochondria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-CoA produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the same substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the limitation of ketogenesis in newborn-pig liver is due to a very low amount and activity of mitochondrial HMG-CoA synthase as compared with rat liver mitochondria, and suggest that this could promote the accumulation of acetyl-CoA and/or beta-oxidation products that in turn would decrease the overall rate of fatty acid oxidation in newborn- and adult-pig livers.
Duée
P H
PH
Unité d'Ecologie et de Physiologie du Système Digestif, INRA, 78352 Jouy-en-Josas, France.
Pégorier
J P
JP
Quant
P A
PA
Herbin
C
C
Kohl
C
C
Girard
J
J
D000818:Animals; D000831:Animals, Newborn; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D007657:Ketone Bodies / Q000096:biosynthesis*; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000378:metabolism*; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction; D011048:Polarography; D051381:Rats; D013552:Swine
D007657:Ketone Bodies; D009829:Oleic Acids; D019301:Oleic Acid; D006904:Hydroxymethylglutaryl-CoA Synthase