Benjamin Wittels

Lipid metabolism in the newborn heart.

In recent years long chain fatty acids have been shown to be the principal metabolic fuel of the adult heart (1-3). For the tissues of the mammalian fetus, however, carbohydrates rather than lipids appear to serve as the primary source of energy (4, 5). This difference in energy metabolism related to maturation suggested that the heart of the newborn, in contrast to that of the adult, might be unable to utilize long chain fatty acids and perforce must rely on glucose as the major substrate for energy production. After the observation that the rate of long chain fatty acid oxidation in tissues was enhanced by carnitine (y-trimethyl ammonium 18-hydroxybutyrate) (6), intensive investigation was undertaken to elucidate the mechanism of action of this compound. Carnitine, a normal constituent of many tissues, is especially abundant in myocardium (7, 8). From the evidence obtained in several laboratories (9, 10), it has been proposed that carnitine effects a stimulation of long chain fatty acid oxidation by functioning as a carrier of activated long chain fatty acyl groups from the extramitochondrial cytoplasm to the intramitochondrial sites of fatty acid oxidation. In this operation, a reversible transesterification between long chain fatty acyl CoA and carnitine has been demonstrated whereby long chain fatty acylcarnitine is formed. As acylcarnitine esters, the long chain fatty acids can be translocated across the mitochondrial membrane, which is relatively impermeable to acyl CoA molecules. The transesterification reaction is catalyzed by a long chain fatty acyl CoA-carnitine transferase, which has been

The effect of thyroxine on lipid and carbohdrate metabolism in the heart.

The administration of thyroxine to a number of experimental animals has resulted in marked structural and metabolic changes in the myocardium. Thyroxine has been shown to produce myocardial hypertrophy (1, 2) and to increase oxygen consumption and fatty acid utilization by the heart (3). In the dog made hyperthyroid by the administration of large doses of thyroxine, increased free fatty acid utilization by the heart was accompanied by a decreased uptake of glucose (3). In this communication data are presented which show that the administration of i-thyroxine to guinea pigs resulted in an increased rate of long chain fatty acid oxidation and a decreased rate of glucose oxidation by myocardial homogenates. The stimulatory effect on fatty acid oxidation was associated with elevated concentrations of free carnitine and acylcarnitines and increased long chain acyl coenzyme A (CoA)-carnitine acyltransferase (CAT) activity. The decreased glucose oxidation was associated with elevated levels of myocardial hexosemonophosphates and citrate. Citrate, the tissue concentration of which is increased by enhanced fatty acid oxidation, has been identified as one of several compounds that exert rate-controlling influences on glycolysis by inhibiting the activity of phosphofructokinase (PFK) (4, 5).

The effect of diphtheria toxin on carnitine metabolism in the heart.

Abstract 1. 1. In cardiac homogenates from guinea-pigs given diphtheria toxin, a decreased rate of palmitylcarnitine synthesis and of palmitic acid oxidation is associated with a depletion of myocardial carnitine. The addition of carnitine to the homogenates restores the rates of both palmitylcarnitine synthesis and palmitate oxidation. 2. 2. In view of the role of carnitine in the transport of long-chain fatty acids from extra- to intramitochondrial sites, it is postulated that carnitine depletion in the myocardium effected by diphtheria toxin results in a depressed rate of long-chain fatty acid oxidation by impairing the rate of translocation of the long-chain fatty acids into the mitochondria.

Energy substrate metabolism in fresh and stored human platelets

The latent capacity of human platelets for oxidizing several important energy-yielding substrates has been revealed by hypoosmolaric incubation conditions. The data show that the human platelet has a considerable capacity to oxidize both glucose and long-chain fatty acids. Long-chain fatty acids appear to rank favorably with glucose as a potential energy substrate. In a number of mammalian tissues, (-)-carnitine serves to regulate the rate at which long-chain fatty acids are oxidized. Evidence was obtained which suggests that (-)-carnitine functions in a similar role in the platelet. After storage of human platelets at 4 degrees C for 24 hr, the oxidative capacity for glucose was reduced by approximately 25% and for long-chain fatty acids by almost 50%. Investigation of the component parts of the metabolic pathways indicated that a marked decrease in the capacity of the Krebs cycle could be responsible for the decrement in energy substrate oxidation.

Modification of phospholipid metabolism in human red cells by primaouine A possible mechanism in drug-induced hemolysis

Abstract Primaquine stimulated the incorporation of 1- 14 C-labeled long chain fatty acids into lecithin of the intact red cell but inhibited their incorporation into phosphatidylethanolamine. This differential effect of primaquine on phospholipid synthesis was shown to be controlled by the amount of the specific lysophospholipid available to the red cell. In this capacity the lysophospholipids functioned as substrates rather than as physical agents. Based on their accessibility or binding affinity to albumin, two pools of lysolecithin could be defined in the intact red cell. Removal of the accessible lysolecithin from the red cell resulted in a marked increase of osmotic fragility in the presence of primaquine. Virtual restoration of osmotic resistance could be effected by the replacement of the lysolecithin. It is proposed that a pool of lysolecithin bound to the red cell contributes to the osmotic stability of the cell and that primaquine induced hemolysis is related to a depletion of this pool consequent to an enhanced rate of conversion of lysolecithin to lecithin.

Enzyme affinity in the acylation of lysophosphatidylcholine

Analogues of 1-palmitoyl-sn-glycero-3-phosphorylcholine were used to ascertain the respective roles of the 1-palmitoyl-sn-glycero and choline groups in binding this substrate to the transferase catalyzing the acylation reaction. 1-Palmitoyl-sn-glycero-3-phosphorylhomocholine proved to be an effective competitive inhibitor whereas 1-palmitoyl-2-deoxyglycero-3-phosphorylcholine was totally ineffective. The data support the view that the 1-palmitoyl-sn-glycero group plays the major role in determining enzyme affinity whereas the choline group functions primarily in the subsequent steps of the acylation reaction.