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

Abstract

1. Measurements-have been made of the hepatic metabolites in normal and thyroidectomized rats and of enzymes of the glycolytic route, the pentose phosphate pathway, the tricarboxylic acid cycle and of lipogenesis together with the flux of glucose through alternative pathways of glucose metabolism and into lipid.2. There is 11 significant fall in the content of ADP, AMP, citrate, long-chain acyl-CoA derivatives and a h e of 3-phosphoglycerate, 2-phosphoglycerate and phosphoenolpyruvate following thyroidecto. Iy. The observed changes in the glycolytic intermediates may be correlated with the increased acLivity 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-hydi-oxybutyrate 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 mitochondria1 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 decline 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. E~~~~~ Commission code numbers are given in cyclic GMP, guanosine 3' : 5'-monophosphate.Tahle4.

Fatty acid biosynthesis in adipose tissue and lung subcellular fractions of thyrotoxic rats

“…In [ 191 a similar behaviour for fatty acid synthetase in liver and adipose tissue was determined as far as both nutritional factors and the diabetic state and insulin administration were concerned. In [20], using thyroidectomized rats, certain glucose and lipid metabolism enzymes in adipose tissue were also shown to behave similarly to those in liver. Table 3 reports the effect of the thyrotoxic state on microsomal fatty acid chain elongation synthesis in the 2 tissues under investigation.…”

Bio-Inorganic Regulation of Pathways of Carbohydrate and Lipid Metabolism

“…The conversion of 14C-labelled glucose to 14C02 and 14C-lipid by adrenal glands was essentially as described previously [9,10]. Paired adrenal glands were cut in half with a sharp razor blade and incubated for 1 h in plastic tubes, with a centre well, in 2.…”

“…En zymes of the glycolytic route, the pentose phosphate pathway, lipogenesis and of the glucuronate-xylulose route were estimated as previously described [9,10]. The Enzyme Commission nomenclature numbers are given in table I.…”

Age-Related Changes in Enzymes of Rat Brain

“…The brain extracts were prepared as previously de scribed [11] using an ice-cold medium containing 0.25 mol/1 sucrose, 20 mmol/1 tnethanolamine buffer pH 7.4 and 0.1 mmol/1 dithiothreitol, using a Potter homogenizer with a Teflon plunger. The subsequent treatment of the extracts and the methods used for the measurement of enzyme activities were as reported earlier [11][12][13], Brain slices were prepared using a multiple-blade sheer as previously described [10]. The Table I.…”