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 se nsitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inh ibition is high, as suggested by the very low concentration of malonyl -CoA required for 50% inhibition of CPT I (IC50). of oleate oxidation and ketogenesis are respectively 70 and 80 % lower in mitochondria iso lated from newborn-pig liver than from starved-adult-rat liver mitocho ndria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-Co A produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the sam e substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the l imitation of ketogenesis in newborn-pig liver is due to a very low amo unt and activity of mitochondrial HMG-CoA synthase as compared with ra t liver mitochondria, and suggest that this could promote the accumula tion of acetyl-CoA and/or beta-oxidation products that in turn would d ecrease the overall rate of fatty acid oxidation in newborn- and adult -pig livers.