Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes

Abstract

The temporal changes in oleate oxidation, lipogenesis, malonyl-CoA concentration and sensitivity of carnitine palmitoyltransferase I (CPT 1) to malonyl-CoA inhibition were studied in isolated rabbit hepatocytes and mitochondria as a function of time after birth of the animal or time in culture after exposure to glucagon, cyclic AMP or insulin. (1) Oleate oxidation was very low during the first 6 h after birth, whereas lipogenesis rate and malonyl-CoA concentration decreased rapidly during this period to reach levels as low as those found in 24-h-old newborns that show active oleate oxidation. (2) The changes in the activity of CPT I and the IC50 (concn. causing 50% inhibition) for malonyl-CoA paralleled those of oleate oxidation. (3) In cultured fetal hepatocytes, the addition of glucagon or cyclic AMP reproduced the changes that occur spontaneously after birth. A 12 h exposure to glucagon or cyclic AMP was sufficient to inhibit lipogenesis totally and to cause a decrease in malonyl-CoA concentration, but a 24 h exposure was required to induce oleate oxidation. (4) The induction of oleate oxidation by glucagon or cyclic AMP is triggered by the fall in the malonyl-CoA sensitivity of CPT I. (5) In cultured hepatocytes from 24 h-old newborns, the addition of insulin inhibits no more than 30% of the high oleate oxidation, whereas it stimulates lipogenesis and increases malonyl-CoA concentration by 4-fold more than in fetal cells (no oleate oxidation). This poor effect of insulin on oleate oxidation seems to be due to the inability of the hormone to increase the sensitivity of CPT I sufficiently. Altogether, these results suggest that the malonyl-CoA sensitivity of CPT I is the major site of regulation during the induction of fatty acid oxidation in the fetal rabbit liver.

Role of insulin in hepatic fatty acid partitioning: emerging concepts

“…Similarly, reversal of the effects of starvation or streptozotocininduced diabetes in rats only starts 6 h after refeeding of the animals and is not complete even after 12 h after the start of refeeding [66] or insulin treatment [67] respectively. The requirement for several hours to achieve the observed modification of CPT I kinetics has been confirmed in experiments using cultured hepatocytes exposed to insulin or glucagon [63,69] and in rats subjected to a hyperinsulinaemic\euglycaemic clamp [70]. The time scale over which these changes occur is commensurate with the involvement of changes in lipid composition of the mitochondrial outer membrane (see above) in determining the properties of CPT I.…”

The Contribution of Glycolysis, Glucose Oxidation, Lactate Oxidation, and Fatty Acid Oxidation to ATP Production in Isolated Biventricular Working Hearts from 2-Week-Old Rabbits

“…Malonyl CoA, which is synthesized from acetyl CoA by acetyl CoA carboxylase, may be important in this regard, because it is a key regulator of CPT 1 in the heart (22,23). In liver, a dramatic decrease in malonyl CoA concentration and sensitivity of CPT 1 to malonyl CoA occurs after birth (24). Whether this is the case in neonatal hearts has yet to be determined.…”

Sensitivity of inhibition of rat liver mitochondrial outer-membrane carnitine palmitoyltransferase by malonyl-CoA to chemical- and temperature-induced changes in membrane fluidity

“…It is evident from this study that the relatively modest changes in fluidity achieved with benzyl alcohol are of sufficient magnitude to effect changes in IC50 for malonyl-CoA of the same order as those observed in transitions between physiological states. Such a mechanism would explain why changes in malonyl-CoA sensitivity in vivo [15,16] or in cultured hepatocytes [26] only occur over the long term (12-24 h), as, presumably, they would depend on changes in the rates of synthesis and degradation of specific membrane lipids. Experimental verification of this proposal should emerge from studies on changes in the lipid composition of pure outer membranes with physiological state, and of the effects of any such changes on the fluidity of the membranes as measured with the use of mobility probes.…”