Independence of Cholesterol and Fatty Acid Biosynthesis from Cyclic Adenosine Monophosphate Concentration in the Perfused Rat Liver

Cyclic adenosine 3':5'-monophosphate (cyclic AMP), when added in a concentration of 5 mm to incubations of rat liver slices with [1-14C]acetate or [1-14C]octanoate, was found to depress markedly both cholesterol and fatty acid biosynthesis but not CO2 or ketone body production. The inhibitory effects of the nucleotide were lost when its concentration was reduced to 0.5 mm. These findings, therefore, confirm and extend those made by others. However, it also was observed that perfusion of rat livers with the above mentioned substrates in the presence of sufficient glucagon to raise the tissue cyclic AMP level by at least 50-fold was totally without effect on rates of cholesterol or fatty acid synthesis. In addition, such treatment of the livers failed to reduce the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase in subsequently isolated microsomes. It is concluded that in the intact liver cholesterol and fatty acid synthesis are independent of acutely induced changes in the intracellular cyclic AMP concentration over a very wide physiological range.