The Effects of Glucagon, Dibutyryl Cyclic Adenosine 3',5'-Monophosphate, and Concentration of Free Fatty Acid on Hepatic Lipid Metabolism

Abstract

Abstract The effects on the isolated perfused rat liver of glucagon, dibutyryl 3',5'-adenosine monophosphate (dibutyryl cyclic AMP), and oleic acid were studied with particular reference to actions on hepatic metabolism of lipids. The rate of uptake of oleic acid by livers from normal fed animals was proportional to the concentration of free fatty acid in the medium and generally was not altered significantly by addition of glucagon to the medium. Glucagon stimulated the rate of ketogenesis and inhibited the output of triglyceride by the liver. The output of ketone bodies by the liver, which was a function of the concentration of oleic acid in the medium, was stimulated by glucagon at concentrations of free fatty acids less than 1.0 to 1.5 mm; at higher concentrations, rates of ketogenesis were similar whether or not glucagon was added to the perfusate. The output of triglyceride, which was dependent on the concentration of oleic acid in the perfusate, was depressed by glucagon at all concentrations of free fatty acids. The net accumulation of triglyceride in the liver was a function of the concentration of fatty acid in the medium and did not appear to be affected significantly by glucagon. The uptake of oleic acid from the medium was not affected by dibutyryl cyclic AMP, but the nucleotide stimulated production of ketone bodies and inhibited output of triglyceride. The output of glucose and urea by liver was stimulated by glucagon. The output of glucose also was increased by dibutyryl cyclic AMP; in these experiments, even though the mean output of urea when cyclic AMP was added exceeded the control, the differences were not statistically significant. It is postulated that hepatic rates of oxidation and ketogenesis from free fatty acids perfusing the liver are increased by glucagon and by cyclic AMP. Glucagon and cyclic AMP may exert their actions in part by direct stimulation of oxidative pathways and in part by inhibition of biosynthetic pathways as the formation and release of triglyceride and the very low density lipoprotein.