Depression of Reducing‐Equivalent Translocation from Substrate to Oxygen in Hepatic Metabolism of Sorbitol or Glycerol in Hypothyroidism

The metabolism of sorbitol or glycerol in isolated liver cells from hypothyroid rats was studied in order to determine whether the rate of reducing‐equivalent translocation limits hepatic metabolism in a hypometabolic state. Rates of utilization of these substrates were compared with analogous data in euthyroid animals. When a saturating concentration of sorbitol or glycerol was added to the cells, gluconeogenic rates were only 54% and 29%, respectively, of the values in cells from euthyroid rats. Reducing‐equivalent translocation to O 2 , as well as oxygen consumption by the cells, was depressed in a similar fashion. However, addition of pyruvate, acting as a cytoplasmic hydrogen acceptor, increased the utilization of sorbitol by 1.75 μmol. g −1 . min −1 and that of glycerol by 0.50 μmol. g −1 . min −1 . This maneuver restored sorbitol utilization equal to rates in controls, whereas it partially corrected the depression in glycerol metabolism resulting from hypothyroidism. It was inferred from the data that the disposal of hydrogen generated in the cytoplasm is a limiting factor in the metabolism of sorbitol or glycerol in hypothyroid animals. At the same time rates of gluconeogenesis from fructose or dihydroxyacetone, which utilize similar pathways, were not depressed. It was concluded that the enzymes of the gluconeogenic route are not responsible for the diminished metabolism of sorbitol or glycerol in hypothyroidism; rather a diminished capacity for hydrogen traslocation between cell compartments results in lowered rates of substrate oxidation, and subsequently, decreased rates of gluconeogenesis. Pathways of hydrogen translocation that are depressed in hypothyroidism and responsible for the decreased utilization of sorbitol or glycerol were investigated by the use of specific inhibitors. In the hypothyroid state hydrogen translocation from each substrate was depressed by 0.91–0.96 μmol. g −1 . min −1 . It was calculated that 82% and 88% of the depressed metabolism of sorbitol or glycerol, respectively, was due to decreased activity of a pathway insensitive to rotenone and sensitive to antimycin, most likely involving mitochondrial glycerol‐phosphate dehydrogenase. Most of the remaining loss was attributed to a diminished capacity of shuttles which were sensitive to fluoromalate and had malate dehydrogenase as a component. These studies support the concept that thyroid hormone may play an important role in the regulation of hepatic metabolism by modulating the capacities of the shuttles which translocate reducingequivalents between cell compartments.