Inhibition of Fatty Acid Stimulation of Gluconeogenesis by (+)-Decanoylcarnitine in Perfused Rat Liver

Abstract

Oleic acid produced a two- to three-fold stimulation of glucose production from lactate in perfused livers from fasted rats. This effect was completely blocked by (+)-decanoylcarnitine, a known inhibitor of (−)-carnitine palmityltransferase. Activation of fatty acids to the acyl CoA esters was not inhibited. Neither β-oxidation of octanoate, nor its stimulatory effect on gluconeogenesis was blocked by (+)-decanoylcarnitine. The results show that in the intact liver, the oxidation of long-chain but not short-chain fatty acids proceeds almost entirely through carnitine-dependent pathways. Changes in the tissue levels of metabolic intermediates after addition of oleic acid show that the increased rate of gluconeogenesis was caused by a stimulation of the pyruvate carboxylase step. Attendant increases in the levels of acetyl CoA and NADH are consistent with the proposal that the mitochondrial levels of these intermediates control carbohydrate metabolism by diverting pyruvate from oxidation towards the synthesis of glucose. A further control site was identified upon fatty acid addition in the region of the phosphofructokinase and fructose diphosphatase reactions. There was no evidence for control at either of these steps by adenine nucleotides, but a marked rise of citrate was consistent with a postulated inhibition of phosphofructokinase. All the changes in the levels of intermediates of the gluconeogenic pathway and citric acid cycle induced by oleic acid were blocked by (+)-decanoylcarnitine. The failure of oleic acid to increase acetyl CoA and citrate levels in the presence of (+)-decanoylcarnitine explains its failure to stimulate gluconeogenesis under these conditions. It is concluded that the effect of fatty acids on gluconeogenesis is determined by their rate of oxidation and not by their concentration in the perfusion fluid. The significance of these findings in relation to the interactions of carbohydrate and fatty acid metabolism in vivo in the normal, starved and diabetic states is discussed.