The Effect of Raising the NAD + Content on the Pathways of Carbohydrate Metabolism and Lipogenesis in Rat Liver

1 Measurements have been made of the steady‐state level of a number of intermediates of the pathways of glucose metabolism and of lipogenesis and the rate of conversion of [ 14 C]glucose into 14 C‐labelled lipid and 14 CO 2 following pre‐treatment of rats with a single injection of nicotinamide (4 or 6 h). 2 Increased activities of phosphofructokinase, 3‐phosphoglyceraldehyde dehydrogenase/3‐phosphoglycerate kinase and pyruvate kinase, as shown by the application of the cross‐over theorem, indicated that these enzymes may be sites of metabolic control. 3 The increased hepatic content of NAD + is accompanied by an increase of free oxidized to reduced nicotinamide nucleotides in the cytoplasm and mitochondria, as calculated from the values of the intermediates, at both time intervals. 4 The liver content of glucose‐6‐phosphate, glycerol‐1‐phosphate, citrate and malate were decreased by the treatment; the adenine nucleotides, fatty acyl CoA, acetyl CoA were unchanged, while the free CoA increased. Fatty acids were considerably increased 4 h after nicotinamide but were below control level at 6 h. 5 The incorporation of [1‐ 14 C]‐ and [U‐ 14 C]glucose into 14 CO 2 was not changed but the incorporation of [6‐ 14 C]glucose, [2‐ 14 C]pyruvate and [2‐ 14 C]lactate into 14 CO 2 were all increased. 6 The incorporation of all labelled substrates into 14 C‐labbelled lipids was inhibited at both 4 h and 6 h after nicotinamide, more strongly at 4 h. 7 Evidence is presented that the increased activity of the tricarboxylic acid cycle is due to the more oxidized state of the mitochondrial nicotinamide nucleotides. 8 The inhibition of lipogenesis is considered from the points of view of glycerol‐1‐phosphate shortage, fatty acyl CoA inhibition and hydrogen limitation.