A number of agents that mimic the ability of the thyroid hormone, T3, to decrease plasma cholesterol levels are described; one is as effective as T3 at reducing cholesterol levels and stimulating liver function, but has very little effect on cardiac function and is thus less likely to be toxic. The agent may be useful in the treatment of atherosclerosis.

1. Fructose 1,6-diphosphatase has been purified tenfold from rat liver. The final preparation was not contaminated by either glucose 6-phosphatase or phosphofructokinase. The properties of the enzyme have been investigated in an attempt to define factors that could be of revelance to metabolic control of fructose 1,6-diphosphatase activity. 2. The metal ions Fe(2+), Fe(3+) and Zn(2+) inhibited the activity of fructose 1,6-diphosphatase even in the presence of an excess of mercaptoethanol; other metal ions tested had no effect. The inhibition produced by Zn(2+) was reversed by EDTA, but that produced by either Fe(2+) or Fe(3+) was not reversible. 4. The enzyme has a very low K(m) for fructose 1,6-diphosphate (2.0mum). Concentrations of fructose 1,6-diphosphate above 75mum inhibited the activity; however, even at very high fructose 1,6-diphosphate concentrations only 70% inhibition was obtained. 5. The activity was also inhibited by low concentrations of AMP, which lowered V(max.) and increased K(m) for fructose 1,6-diphosphate. Evidence is presented that suggests that AMP can be defined as an allosteric inhibitor of fructose 1,6-diphosphatase. 6. The inhibitions by both fructose 1,6-diphosphate and AMP were extremely specific. Also, the degree of inhibition was not affected by the presence of intermediates of glycolysis, of the tricarboxylic acid cycle, of amino acid metabolism or of fatty acid metabolism. 7. It is suggested that the intracellular concentrations of AMP and fructose 1,6-diphosphate could be of significance in controlling the activity of fructose 1,6-diphosphatase in the liver cell. The possible relationship between these intermediates and the control of gluconeogenesis is discussed.

Twenty-nine novel 3'-substituted derivatives of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) have been synthesized by using established methods and by a new route involving manipulation of a 3'-formyl intermediate. In vitro hormone receptor binding (to intact nuclei) and in vivo thyromimetic activity (induction of mitochondrial 3-phosphoglycerate oxidoreductase, GPDH) were measured in rat liver and heart for these new analogues and for the 18 previously reported 3'-substituted 3,5-diiodo-L-thyronines. Analysis of the binding data using theoretical conformational and quantitative structure-affinity methods implies that the 3'-substituent recognition site on the thyroid hormone receptor is hydrophobic and limited in depth to the length of the natural iodo substituent, but has sufficient width to accommodate a phenyl or cyclohexyl group. Receptor binding is reduced by approximately 10-fold in 3'-acyl derivatives which form strong intramolecular acceptor hydrogen bonds with the adjacent 4'-hydroxyl. The compounds studied showed no differences in their relative affinities for heart and liver nuclei, suggesting that receptors in these tissues are similar. However, the relationships between thyromimetic activity (induction of GPDH) and nuclear binding showed some tissue differences. A high correlation between activity and binding is observed for full agonists in the heart, but an equally significant correlation for the liver data is only seen when 3'-substituent bulk (molar refractivity) is included in the analysis. These results suggest the possibility that differential tissue penetration or access to receptors may occur in vivo.

1. Glucose uptake or glucose formation has been studied in kidney cortex slices to investigate metabolic control of phosphofructokinase and fructose-diphosphatase activities. 2. Glucose uptake is increased and glucose formation is decreased by anoxia, cyanide or an uncoupling agent. Under these conditions the intracellular concentrations of glucose 6-phosphate and ATP decreased whereas that of fructose diphosphate either increased or remained constant, and the concentrations of AMP and ADP increased. 3. Glucose uptake was decreased, and glucose formation from glycerol or dihydroxyacetone was increased, by the presence of ketone bodies or fatty acids, or after starvation of the donor animal. Under these conditions, the concentrations of glucose 6-phosphate and citrate were increased, whereas those of fructose diphosphate and the adenine nucleotides were unchanged (see also Newsholme & Underwood, 1966). 4. It is concluded that anoxia and cell poisons increase glucose uptake and decrease gluconeogenesis by stimulating phosphofructokinase and inhibiting fructose diphosphatase, whereas ketone bodies, fatty acids or starvation increase gluconeogenesis and decrease glucose uptake through the citrate inhibition of phosphofructokinase.

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