Precursor For Fatty Acid Synthesis Research Articles

Pathways of fatty acid biosynthesis: Conversion of glutamate carbon to fatty acid carbon via citrate by lactating mouse mammary gland and adenocarcinoma of mouse mammary gland

1. 1. As a part of a study of fatty acid biosynthesis, we have investigated the utilization of 14C-labeled glutamate, lactate and acetate by slices of lactating mouse mammary gland and adenocarcinoma of mouse mammary gland. 2. 2. It was found that slices of both tissues incorporated 14C-labeled carbon from [2- 14C] and (5- 14C]glutamate, [2- 14C]lactate and [I- 14C]acetate, but not from [I- 14C]-glutamate, into fatty acids. Regardless of the labeled substrate used, its incorporation into fatty acids was significantly higher in the normal tissue. 3. 3. Analyses of the fatty acids synthesized from [5- 14C]glutamate and [I- 14C]-acetate by the normal tissue indicated incorporation entirely via a de novo pathway, giving rise to an average chain length of 10–14 carbons. In the neoplasm, formation of fatty acids from these substrates seems to proceed via the elongation pathway predominantly, giving rise to an average chain length of 16 carbons. 4. 4. The data indicate the operation of a metabolic pathway which permits the conversion of glutamate through α-ketoglutarate, isocitrate, cis-aconitate and citrate to acetyl CoA and oxalacetate in the lactating mouse mammary gland and the mammary adenocarcinoma. The possible significance of this backward pathway in the supply of precursors for fatty acid synthesis is discussed.

Studies on the Metabolism of Adipose Tissue: XIX. AN EVALUATION OF THE MAJOR PATHWAYS OF GLUCOSE CATABOLISM AS INFLUENCED BY ACETATE IN THE PRESENCE OF INSULIN

Abstract Rat epididymal fat pads were incubated at 37° in bicarbonate buffer, pH 7.4, with glucose (10 mm) or with glucose plus acetate (15 mm), in the presence of insulin (1000 microunits per ml). The net gas exchange, total CO2 production, O2 consumption, glucose utilization, lactate and glycerol production, and radioactive carbon incorporation into CO2 and fatty acids were measured, with the use of matched pieces of tissue, in the presence of (a) uniformly labeled glucose-14C, (b) uniformly labeled glucose-14C plus unlabeled acetate, (c) unlabeled glucose and acetate-1,2-14C, and (d) glucose-6-14C and unlabeled acetate. The results permitted the estimation of the quantitative flow of glucose and acetate carbon into the major metabolic pathways of adipose tissue. It was found that when glucose and acetate were present together the flow of glucose carbon through the pentose cycle increased 83% and total fatty acid synthesis 60% above that seen with glucose alone. Part of the increased fatty acid synthesis was due to a greater flow of glucose carbon to acetyl coenzyme A, brought about entirely by the increased production of glyceraldehyde phosphate in the pentose cycle. It was calculated that the pentose cycle provided 65% of the reduced nicotinamide adenine dinucleotide phosphate needed for reduction to fatty acid of the acetyl-CoA formed from glucose, but that this cycle furnished all the extra reducing equivalents needed when acetate was also available as a precursor for fatty acid synthesis. This difference is attributed to the production of reduced coenzymes in the formation of acetyl-CoA from glucose but not from acetate. The conversion of a portion of these reduced coenzymes into NADPH for use in fatty acid synthesis, and the reaction of of the remainder with oxygen, are discussed. It is concluded that the rate of these reactions may limit conversion of glucose to fat in adipose tissue maximally stimulated by insulin. A limitation does not appear to be set by the rate at which any of the following processes can proceed: (a) glucose uptake, (b) NADPH formation by the pentose cycle, (c) conversion of acetyl-CoA to fatty acids, (d) consumption of oxygen and production of adenosine triphosphate.

QUANTITATIVE ASPECTS OF GLUTAMATE UTILIZATION BY RAT ADIPOSE TISSUE AND LIVER IN VITRO: EFFECT OF PERIODICITY OF EATING

The activity of two pathways supplying substrate for lipogenesis was enhanced in adipose tissue of meal-fed rats. One of these pathways, the forward pathway, involves the entry of α-ketoglutarate into the mitochondria, and metabolism via the Krebs cycle; the second pathway involves the backward flow of α-ketoglutarate to citrate in the cytoplasm, and cleavage of citrate to supply acetyl-CoA. Meal feeding increased fatty acid synthesis via the forward and backward pathways, but the relative amount of glutamate incorporated into lipid via the backward pathway decreased as a result of meal eating. The relative importance of the backward and forward pathways to the incorporation of α-ketoglutarate into fatty acid appeared to be similar for liver and adipose tissue. Lipogenesis from glutamate was significantly greater in adipose tissue incubated in bicarbonate than in phosphate buffer; however, the relative differences between tissues from meal-fed rats and from those fed ad libitum were similar in the two buffers. The possible importance of the backward pathway in the supply of precursors for fatty acid synthesis is discussed.