Control of Gluconeogenesis in Liver

Abstract

Abstract The possible roles of fatty acids in the regulation of gluconeogenesis and in the gluconeogenic action of glucagon were investigated in the isolated perfused rat liver. Oleate in complex with albumin did not alter glucose production or 14C-glucose formation in livers from fed rats perfused with saturating or lower concentrations of 14C-lactate. It also did not affect glucose utilization or 14C-glucose disappearance in livers from fed or fasted rats perfused with 18 mm 14C-glucose. Unbound oleate, infused at the rate of 2 µmoles per min in livers from fed rats, increased ketogenesis 3-fold but did not alter glucose production or gluconeogenesis. At a rate of 4 µmoles per min, it increased ketogenesis 5-fold, glucose synthesis from lactate by 50%, and total glucose production by about 30%. The stimulation of gluconeogenesis disappeared at still higher infusion rates although marked ketogenesis and glycogenolysis still occurred. Unbound oleate frequently produced detectable increases in tissue adenosine 3',5'-monophosphate (cyclic AMP). Unbound octanoate infused at 5 µmoles per min increased ketogenesis, glycogenolysis, gluconeogenesis, and cyclic AMP accumulation. Carnitine did not affect the rates of glucose production, gluconeogenesis, or ketogenesis in livers from fed rats and did not alter the effects of unbound oleate on these processes. In livers from fasted rats in which gluconeogenesis had been inactivated by an initial perfusion without substrate, oleate in complex with Fraction V serum albumin increased glucose formation from lactate by about 30% and enhanced glycogen deposition and ketogenesis. Some albumin samples had a stimulatory effect on gluconeogenesis which was unaltered by removal of fatty acids. Infusions of unbound oleate or octanoate increased gluconeogenesis by 50% and reduced or did not alter glycogen formation. Ketogenesis was stimulated manyfold. In contrast to the above effects of fatty acids, glucagon increased gluconeogenesis from lactate more than 2-fold but did not stimulate ketogenesis in livers from fed or fasted rats. The gluconeogenic effect of oleate-albumin complex or unbound oleate was additive with that of a maximally effective concentration of glucagon. Mechanisms proposed for the gluconeogenic and ketogenic actions of glucagon are discussed. It is concluded that fatty acids probably do not play a physiological role in the rapid regulation of hepatic gluconeogenesis, and that glucagon does not stimulate gluconeogenesis by activating hepatic lipolysis. The physiological regulation of ketogenesis appears to involve primarily the control of fatty acid supply to the liver, i.e. the regulation of lipolysis in fat tissue. Regulation by glucagon at the hepatic level is of minor importance.