Effects of Hypothyroidism, Hyperthyroidism, and Thyroxine on Net Synthesis of Plasma Proteins by the Isolated Perfused Rat Liver: MODULATION OF THE RESPONSE TO INSULIN PLUS CORTISOL IN THE NET SYNTHESIS OF ALBUMIN, FIBRINOGEN, α1-ACID GLYCOPROTEIN, α2-(ACUTE PHASE) GLOBULIN, AND HAPTOGLOBIN

Abstract The isolated rat liver perfused for 12 hours has been used to study effects of added thyroxine and effects of hyperthyroidism and hypothyroidism in the liver donor on net biosynthesis of five specific plasma proteins, namely, rat serum albumin, fibrinogen, α1-acid glycoprotein, α2-(acute phase) globulin, and haptoglobin. Hypothyroidism was produced either by surgical thyroidectomy or by feeding methimazole (0.5 g per kg) in the powdered diet; hyperthyroidism was induced by injecting normal rats with thyroxine (10µg/100g body weight subcutaneously per day). The metabolic status of each animal was confirmed by O2 consumption measurements. The basic perfusate consisted of washed bovine red cells suspended in Krebs-Ringer-bicarbonate solution containing bovine serum albumin (3.0 g/100 ml) to which was added nutritional (glucose, amino acids) and hormonal (cortisol, insulin) constituents. When used, thyroxine was added along with the other hormones at the start of perfusion as well as by constant infusion throughout the experiment. Livers from hyperthyroid liver donors synthesized significantly more albumin than those from hypothyroid rats; however, addition of thyroxine to the perfusion of livers from euthyroid and hyperthyroid rats decreased albumin synthesis. Fibrinogen synthesis was not altered significantly among the experimental groups studied here, nor was there any change in the phenomenon of induction, shown previously to be dependent upon the presence of cortisol. Synthesis of α1-acid glycoprotein and α2-(acute phase) globulin was somewhat higher by livers from hypothyroid rats than by those from euthyroid controls, and maximum rates occurred in hyperthyroid livers given a total of 4.0 µg of thyroxine. Haptoglobin synthesis was greater by livers from hyperthyroid rats than by those from normal and hypothyroid donors; the addition of 4.0 µg of thyroxine to the perfusate of normal and hyperthyroid livers increased haptoglobin synthesis while 22.0 µg caused a decrease. Nitrogen balance was estimated for the perfusion system in terms of net cumulative changes in amino acid nitrogen and urea nitrogen in the perfusate and bile. Hyperthyroidism in the liver donor and 4.0 µg of thyroxine in the perfusate resulted in negative nitrogen balance, simultaneously with maximum uptake of glucose and increased oxidation of l-[1-14C]lysine to 14CO2. Positive nitrogen balance was not a requirement for normal or enhanced net synthesis of specific plasma proteins; however, under conditions of extremely negative nitrogen balance, synthesis of acute phase proteins was impaired. Limited data on the dose-response relationship between thyroxine added to the perfusate and the metabolic response of the liver revealed that the addition of 2.0 µg of thyroxine at zero time plus the continuous infusion of an additional 2.0 µg over a 12-hour period elicited optimal anabolic responses.