Effects of thyroid hormone deficiency on the distribution of hepatic metabolites and control of pathways of carbohydrate metabolism in liver and adipose tissue of the rat.

1. Measurements have been made of the hepatic metabolites in normal and thyroidectomized rats and enzymes of the glycolytic route, the pentose phosphate pathway, the tricarboxylic acid cycle and lipogenesis together with the flux of glucose through alternative pathways of glucose metabolism and into lipid. 2. There is a significant fall in the content of ADP, AMP, citrate, long-chain acyl-CoA derivatives and a rise of 3-phosphoglycerate, 2-phosphoglycerate and phosphoenolpyruvate following thyroidectomy. The observed changes in the glycolytic intermediates may be correlated with the increased activity of phosphofructokinase relative to pyruvate kinase and fructose bisphosphatase. 3. The NAD+/NADH quotient of the mitochondrial compartment, calculated from the reactants and Keq of 3-hydroxybutyrate dehydrogenase, becomes significantly more oxidized in hypothyroid animals. The redox state of the cytosolic NAD and NADP couples remains relatively unchanged. 4. The changes in the hepatic content of CoA derivatives and citrate and in the mitochondrial redox state are interpreted as indicating a depressed rate of lipid oxidation. 5. Calculations of the compartmentation of metabolites between the cytosol and mitochondria indicate a very marked decrease in mitochondrial citrate, 2-oxoglutarate and glutamate with smaller changes in aspartate and malate. These changes are interpreted as providing evidence for the importance of modifications in the malate-aspartate shuttle in hypothyroidism; this is further supported by measured changes in the distribution and activities of the component enzymes of the hydrogen shuttles. 6. There is a diminished activity of glucokinase and of enzymes of the glycolytic pathway below phosphofructokinase in livers from hypothyroid rats. The oxidative enzymes of the pentose phosphate pathway, ATP-citrate lyase, 'malic' enzyme and fatty acid synthetase also decrease markedly. There is a striking parallelism between the changes of enzyme profile of liver and adipose tissue in hypothyroidism. 7. Adrenal glands from hypothyroid rats showed a generalized delcine in enzyme activity in parallel with the fall in tissue weight. Cytosolic glycerol-3-phosphate dehydrogenase decreased sharply. 8. The present results are discussed in relation to data in the literature on the increased activities of cyclic AMP and cyclic GMP phosphodiesterases in hypothyroidism, observations which integrate the relationships between anabolic and catabolic pathways of carbohydrate and lipid metabolism with alterations in hormone sensitivity in hypothyroidism.