Inhibition of Glucagon Effects in Perfused Rat Liver by (+)Decanoylcarnitine

Abstract

In perfused livers from fasted rats, glucagon (2 X lop9 M) caused a 75% increase of glucose formation from lactate, a d-fold increase of urea production, and a 50% increase of ketogenesis.However, urea formation could account for only about 10% of the glucose formation.Subsequent addition of oleate caused a further 50% stimulation of gluconeogenesis and a 6-fold rise of ketone body formation.The effects of glucagon and oleate on gluconeogenesis were not additive, since glucagon addition in the presence of oleate had no further effect.The stimulation of gluconeogenesis and ketogenesis produced by oleate was almost completely abolished by (+)decanoylcarnitine, an inhibitor of pahnitylcarnitine transferase.The effects of glucagon, however, were only partially inhibited by (+)decanoylcarnitine.Glucagon, either in the absence or presence of oleate, increased the ratios of lactate to pyruvate and /3-hydroxybutyrate to acetoacetate in the perfusion fluid and in the liver, indicating a more reduced state of the NAD systems in both mitochondrial and cytosolic spaces.Direct measurements of oxidation-reduction changes by surface fluorometry showed that glucagon caused rapid reduction of flavin and pyridine nucleotides.These changes were diminished by prior addition of ( +)decanoylcarnitine.Changes in the tissue contents of intermediates showed two control sites after glucagon addition, one between pyruvate and oxalacetate, and the other between fructose-l ,6-di-P and fructose-6-P.Similar changes were observed when oleate was added at the same time as glucagon.In previous publications it has been shown that interactions at these sites produced by oleate were consistent with observed increases in the tissue contents of acetyl coenzyme A and citrate, which presumably caused an activation of pyruvate carboxylase and an inhibition of phosphofructokinase, respectively.However, in the present experiments, neither acetyl-CoA nor citrate contents were significantly increased by glucagon.These results are interpreted as indicating that either other