A B S T R A C T Studies on the oxidation of oleic and octanoic acids to ketone bodies were carried out in homogenates and in mitochondrial fractions of livers taken from fed and fasted rats. Malonyl-CoA inhibited ketogenesis from the former but not from the latter substrate. The site of inhibition appeared to be the carnitine acyltransferase I reaction. The effect was specific and easily reversible. Inhibitory concentrations were in the range of values obtained in livers from fed rats by others. It is proposed that malonylCoA functions as both precursor for fatty acid synthesis and suppressor of fatty acid oxidation. As such, it might be an important element in the carbohydrate-induced sparing of fatty acid oxidation.

The requirement for carnitine and the malonyl-CoA sensitivity of carnitine palmitoyl-transferase I (EC 2.3.1.21) were measured in isolated mitochondria from eight tissues of animal or human origin using fixed concentrations of palmitoyl-CoA (50 microM) and albumin (147 microM). The Km for carnitine spanned a 20-fold range, rising from about 35 microM in adult rat and human foetal liver to 700 microM in dog heart. Intermediate values of increasing magnitude were found for rat heart, guinea pig liver and skeletal muscle of rat, dog and man. Conversely, the concentration of malonyl-CoA required for 50% suppression of enzyme activity fell from the region of 2-3 microM in human and rat liver to only 20 nM in tissues displaying the highest Km for carnitine. Thus, the requirement for carnitine and sensitivity to malonyl-CoA appeared to be inversely related. The Km of carnitine palmitoyltransferase I for palmitoyl-CoA was similar in tissues showing large differences in requirement for carnitine. Other experiments established that, in addition to liver, heart and skeletal muscle of fed rats contain significant quantities of malonyl-CoA and that in all three tissues the level falls with starvation. Although its intracellular location in heart and skeletal muscle is not known, the possibility is raised that malonyl-CoA (or a related compound) could, under certain circumstances, interact with carnitine palmitoyltransferase I in non-hepatic tissues and thereby exert control over long chain fatty acid oxidation.

No abstract

In the catabolic state with no food intake, the liver generates ketones by breaking down fatty acids. During the nocturnal fast or longer starvation periods, this protects the brain, which cannot oxidize fatty acids. In 1977, we published a study in the JCI noting the surprising realization that malonylCoA, the substrate of fatty acid synthesis, was also an inhibitor of fatty acid oxidation. Subsequent experiments have borne out this finding and furthered our understanding of molecular metabolism.

Metabolism cycles daily between the fed and fasted states. The pathways of energy production are reversible and distinct. In the anabolic (fed) state, the liver stores glucose as glycogen, and fatty acid/triglyceride synthesis is active. In the catabolic (fasted) state, the liver becomes a glucose producer, lipogenesis is slowed, and fatty acid oxidation/ketogenesis is activated. The rate-limiting step for the latter is vested in the carnitine/carnitine palmitoyltransferase (CPT) system, and the off/on regulator of this is malonyl CoA. The AMP-induced protein kinase primarily determines the concentration of malonyl CoA. Four other systems have significant influence: two on fatty acid oxidation and two on lipogenesis. Peroxisome proliferator-activated receptor gamma-1 alpha, a master regulator of metabolism, induces hepatic gluconeogenesis and fatty acid oxidation in the catabolic phase. Deficiency of stearoyl CoA desaturase, although having no role in gluconeogenesis, powerfully induces fatty acid oxidation and weight loss despite increased food intake in rodents. Major stimulators of lipogenesis are carbohydrate-responsive element binding protein and the Insig system. The malonyl CoA-regulated CPT system has been firmly established in humans. The other systems have not yet been confirmed in humans, but likely are active there as well. Activation of fatty acid oxidation has considerable clinical promise for the treatment of obesity, type 2 diabetes, steatohepatitis, and lipotoxic damage to the heart.