A role for carnitine and long chain acylcarnitine in the regulation of lipogenesis

Abstract

In the absence of citrate or other acetyl-CoA carboxylase activator, fatty acid synthesis from acetate or low concentrations of citrate in cell free preparations of rat liver proceeds at a very low rate, analogous to preparations obtained from starved or fat fed animals. Under these conditions, the addition of carnitine results in a further decrease in fatty acid synthesis. In contrast, when high concentrations of citrate are added, carnitine significantly stimulates lipogenesis from both acetate and citrate. The effects observed with carnitine at varying levels of citrate are related both to the availability of carnitine and CoA as well as the ratio of activities of carnitine acetyltransferase and acetyl-CoA carboxylase. In the absence of citrate, acetyl-CoA is shuttled into acetylcarnitine in the presence of carnitine, whereas at high concentrations of citrate and increased acetyl-CoA carboxylase activity, acetyl-CoA is preferentially utilized in the synthesis of fatty acids. In the latter case, carnitine enhances synthesis of long chain fatty acids perhaps by removal of a feed back inhibitor of acetyl-CoA carboxylase (palmitoyl-CoA) as well as providing an activator, palmitoylcarnitine. Both palmitoyl (+) carnitine and palmitoy (−) carnitine stimulate lipogenesis in high speed supernatant liver preparations. Palmitoyl-carnitine in addition stimulates acetyl-CoA carboxylase but does not effect the incorporation of malonyl-CoA into long chain fatty acids in high speed supernatant preparations, suggesting the site of action of long chain acylcarnitine at the acetyl-CoA carboxylase step. Palmitoyl-CoA inhibits a variety of key enzymes involved in the regulation of lipogenesis and glycolysis. Of those enzymes examined, glutamic dehydrogenase, glucose-6-phosphate dehydrogenase, malate dehydrogenase, lactate dehydrogenase, malic enzyme, citrate lyase, citrate synthase, acetyl-CoA carboxylase, and carnitine acetyltransferase, only malic enzyme, malate and lactate dehydrogenases were not inhibited by palmitoyl-CoA. The remaining enzymes were all inhibited by low concentrations of long chain acyl-CoA and of those inhibited only citrate synthase, acetyl-CoA carboxylase, and carnitine acetyltransferase were relieved by palmitoylcarnitine. The results obtained suggest that perhaps the antagonistic effects of palmitoylcarnitine on inhibitions by palmitoyl-CoA may have some physiological significance and need not be necessarily categorized as non-specific.