Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Sep;74(3):705–714. doi: 10.1172/JCI111486

Response of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme to constant infusions of L-triiodothyronine in rats bearing the Walker 256 carcinoma. Evidence for divergent postreceptor regulation of the thyroid hormone response.

J M Tibaldi, N Sahnoun, M I Surks
PMCID: PMC425224  PMID: 6088583

Abstract

To characterize the hepatic response to L-triiodothyronine (T3) in an experimental nonthyroidal disease, we determined the activity of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosol malic enzyme (ME) as a function of the saturation of the nuclear T3 receptor during constant T3 infusions in rats bearing the Walker 256 carcinoma. Groups of control and tumor-bearing rats were infused by minipumps (Alza Corp., Palo Alto, CA) with vehicle, 1.2 or 4.5 micrograms T3/100 body wt per day for 3 d. The range for serum T3 was 47.2 +/- 4.1 to 165 +/- 17.3 ng/dl for the control rats and 13.2 +/- 1.3 to 135 +/- 14.3 ng/dl for the tumor-bearing rats. Nuclear T3 receptor concentration was between 0.41 +/- 0.06 and 0.47 +/- 0.02 ng/mg DNA in control rats and was decreased in tumor-bearing rats to between 0.23 +/- 0.03 and 0.26 +/- 0.03 ng/mg DNA. Nuclear T3 receptor concentrations were not influenced by the T3 infusions. Specifically bound nuclear T3, determined by radioimmunoassay of extracts of isolated nuclei, was decreased nearly 50% in the tumor-bearing rats. However, the calculated percentage saturation of the T3 nuclear receptor remained similar in control and tumor-bearing rats at each level of T3 infusion. Dose-response curves for alpha-GPD and ME were curvilinear and showed an exponential increase in enzyme activity with progressive receptor saturation. In tumor-bearing rats, the activity curves or calculated appearance rate curves for alpha-GPD were shifted significantly upward and to the left, indicating greater sensitivity to T3, and those of ME were shifted downward and to the right, indicating decreased responsiveness to T3. Our findings suggest that cellular factors result in postreceptor amplification of the alpha-GPD response and diminution of the ME response to T3 in tumor-bearing rats. Augmentation of the alpha-GPD response may be a prototype for other hormonal responses that enable the tumor-bearing rat to maintain an apparent euthyroid state in association with decreased serum T3.

Full text

PDF
705

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bermudez F., Surks M. I., Oppenheimer J. H. High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease. J Clin Endocrinol Metab. 1975 Jul;41(1):27–40. doi: 10.1210/jcem-41-1-27. [DOI] [PubMed] [Google Scholar]
  2. Burrows A. W., Cooper E., Shakespear R. A., Aickin C. M., Fraser S., Hesch R. D., Burke C. W. Low serum L-T3 levels in the elderly sick: protein binding, thyroid and pituitary responsiveness, and reverse T3 concentrations. Clin Endocrinol (Oxf) 1977 Oct;7(4):289–300. doi: 10.1111/j.1365-2265.1977.tb01328.x. [DOI] [PubMed] [Google Scholar]
  3. Burrows A. W., Shakespear R. A., Hesch R. D., Cooper E., Aickin C. M., Burke C. W. Thyroid hormones in the elderly sick: "T4 euthyroidism". Br Med J. 1975 Nov 22;4(5994):437–439. doi: 10.1136/bmj.4.5994.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carter J. N., Eastman C. J., Corcoran J. M., Lazarus L. Effect of severe, chronic illness on thyroid function. Lancet. 1974 Oct 26;2(7887):971–974. doi: 10.1016/s0140-6736(74)92070-4. [DOI] [PubMed] [Google Scholar]
  5. Cathcart E. S., Idelson B. A., Scheinberg M. A., Couser W. G. Beneficial effects of methylprednisolone "pulse" therapy in diffuse proliferative lupus nephritis. Lancet. 1976 Jan 24;1(7952):163–166. doi: 10.1016/s0140-6736(76)91272-1. [DOI] [PubMed] [Google Scholar]
  6. Chopra I. J., Solomon D. H., Chopra U., Wu S. Y., Fisher D. A., Nakamura Y. Pathways of metabolism of thyroid hormones. Recent Prog Horm Res. 1978;34:521–567. doi: 10.1016/b978-0-12-571134-0.50018-1. [DOI] [PubMed] [Google Scholar]
  7. Chopra I. J., Solomon D. H., Chopra U., Young R. T., Chua Teco G. N. Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine. J Clin Endocrinol Metab. 1974 Sep;39(3):501–511. doi: 10.1210/jcem-39-3-501. [DOI] [PubMed] [Google Scholar]
  8. Connors J. M., Hedge G. A. Effect of continuous thyroxine administration on thyrotropin secretion in thyroidectomized rats. Endocrinology. 1981 Jun;108(6):2098–2102. doi: 10.1210/endo-108-6-2098. [DOI] [PubMed] [Google Scholar]
  9. Dillmann W. H., Oppenheimer J. H. Glucagon influences the expression of thyroid hormone action: discrepancy between nuclear triiodothyronine receptor number and enzyme responses. Endocrinology. 1979 Jul;105(1):74–79. doi: 10.1210/endo-105-1-74. [DOI] [PubMed] [Google Scholar]
  10. Gavin L. A., McMahon F. A., Castle J. N., Cavalieri R. R. Alterations in serum thyroid hormones and thyroxine-binding globulin in patients with nephrosis. J Clin Endocrinol Metab. 1978 Jan;46(1):125–130. doi: 10.1210/jcem-46-1-125. [DOI] [PubMed] [Google Scholar]
  11. Grajower M. M., Surks M. I. Effect of decreased hepatic nuclear L-triiodothyronine receptors on the response of hepatic enzymes to L-triiodothyronine in tumor-bearing rats. Endocrinology. 1979 Mar;104(3):697–703. doi: 10.1210/endo-104-3-697. [DOI] [PubMed] [Google Scholar]
  12. Hamada S., Nakamura H., Nanno M., Imura H. Tri-iodothyronine-induced increase in rat liver nuclear thyroid-hormone receptors associated with increased mitochondrial alpha-glycerophosphate dehydrogenase activity. Biochem J. 1979 Aug 15;182(2):371–375. doi: 10.1042/bj1820371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ingbar S. H., Braverman L. E. Active form of the thyroid hormone. Annu Rev Med. 1975;26:443–449. doi: 10.1146/annurev.me.26.020175.002303. [DOI] [PubMed] [Google Scholar]
  14. Kumara-Siri M. H., Lee K., Surks M. I. Regulation of thyrotropin secretion in rats bearing the Walker 256 carcinoma. Endocrinology. 1981 Nov;109(5):1760–1768. doi: 10.1210/endo-109-5-1760. [DOI] [PubMed] [Google Scholar]
  15. LEE Y. P., LARDY H. A. INFLUENCE OF THYROID HORMONES ON L-ALPHA-GLYCEROPHOSPHATE DEHYDROGENASES AND OTHER DEHYDROGENASES IN VARIOUS ORGANS OF THE RAT. J Biol Chem. 1965 Mar;240:1427–1436. [PubMed] [Google Scholar]
  16. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  17. Lim V. S., Fang V. S., Katz A. I., Refetoff S. Thyroid dysfunction in chronic renal failure. A study of the pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine. J Clin Invest. 1977 Sep;60(3):522–534. doi: 10.1172/JCI108804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mariash C. N., Kaiser F. E., Schwartz H. L., Towle H. C., Oppenheimer J. H. Synergism of thyroid hormone and high carbohydrate diet in the induction of lipogenic enzymes in the rat. Mechanisms and implications. J Clin Invest. 1980 May;65(5):1126–1134. doi: 10.1172/JCI109766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Martial J. A., Seeburg P. H., Guenzi D., Goodman H. M., Baxter J. D. Regulation of growth hormone gene expression: synergistic effects of thyroid and glucocorticoid hormones. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4293–4295. doi: 10.1073/pnas.74.10.4293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maturlo S. J., Rosenbaum R. L., Pan C., Surks M. I. Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma free thyroid hormone concentrations in patients with nonthyroidal diseases. J Clin Invest. 1980 Sep;66(3):451–456. doi: 10.1172/JCI109875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ohneda A., Aguilar-Parada E., Eisentraut A. M., Unger R. H. Control of pancreatic glucagon secretion by glucose. Diabetes. 1969 Jan;18(1):1–10. doi: 10.2337/diab.18.1.1. [DOI] [PubMed] [Google Scholar]
  22. Oppenheimer J. H., Coulombe P., Schwartz H. L., Gutfeld N. W. Nonlinear (amplified) relationship between nuclear occupancy by triiodothyronine and the appearance rate of hepatic alpha-glycerophosphate dehydrogenase and malic enzyme in the rat. J Clin Invest. 1978 Apr;61(4):987–997. doi: 10.1172/JCI109024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Oppenheimer J. H., Schwartz H. L. Factors determining the level of activity of 3,5,3'-triiodothyronine-responsive hepatic enzymes in the starved rat. Endocrinology. 1980 Nov;107(5):1460–1468. doi: 10.1210/endo-107-5-1460. [DOI] [PubMed] [Google Scholar]
  24. Oppenheimer J. H., Schwartz H. L., Surks M. I. Nuclear binding capacity appears to limit the hepatic response to L-triiodothyronine (T3). Endocr Res Commun. 1975;2(4-5):309–325. doi: 10.1080/07435807509089004. [DOI] [PubMed] [Google Scholar]
  25. Oppenheimer J. H., Schwartz H. L., Surks M. I. Tissue differences in the concentration of triiodothyronine nuclear binding sites in the rat: liver, kidney, pituitary, heart, brain, spleen, and testis. Endocrinology. 1974 Sep;95(3):897–903. doi: 10.1210/endo-95-3-897. [DOI] [PubMed] [Google Scholar]
  26. Oppenheimer J. H., Silva E., Schwartz H. L., Surks M. I. Stimulation of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme by L-triiodothyronine. Characteristics of the response with specific nuclear thyroid hormone binding sites fully saturated. J Clin Invest. 1977 Mar;59(3):517–527. doi: 10.1172/JCI108667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ordene K. W., Pan C., Barzel U. S., Surks M. I. Variable thyrotropin response to thyrotropin-releasing hormone after small decreases in plasma thyroid hormone concentrations in patients of advanced age. Metabolism. 1983 Sep;32(9):881–888. doi: 10.1016/0026-0495(83)90201-9. [DOI] [PubMed] [Google Scholar]
  28. Ramirez G., O'Neill W., Jr, Jubiz W., Bloomer H. A. Thyroid dysfunction in uremia: evidence for thyroid and hypophyseal abnormalities. Ann Intern Med. 1976 Jun;84(6):672–676. doi: 10.7326/0003-4819-84-6-672. [DOI] [PubMed] [Google Scholar]
  29. Reichlin S., Bollinger J., Nejad I., Sullivan P. Tissue thyroid hormone concentration of rat and man determined by radiommunoassay: biologic significance. Mt Sinai J Med. 1973 May-Jun;40(3):502–510. [PubMed] [Google Scholar]
  30. Rosenbaum R. L., Maturlo S. J., Surks M. I. Changes in thyroidal economy in rats bearing transplantable Walker 256 carcinomas. Endocrinology. 1980 May;106(5):1386–1391. doi: 10.1210/endo-106-5-1386. [DOI] [PubMed] [Google Scholar]
  31. Roy A. K. Androgen-dependent synthesis of aplha-2u globulin in the rat: role of the pituitary gland. J Endocrinol. 1973 Feb;56(2):295–301. doi: 10.1677/joe.0.0560295. [DOI] [PubMed] [Google Scholar]
  32. STERLING K., LASHOF J. C., MAN E. B. Disappearance from serum of I131-labeled l-thyroxine and l-triiodothyronine in euthyroid subjects. J Clin Invest. 1954 Jul;33(7):1031–1035. doi: 10.1172/JCI102970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Samuels H. H., Horwitz Z. D., Stanley F., Casanova J., Shapiro L. E. Thyroid hormone controls glucocorticoid action in cultured GH1 cells. Nature. 1977 Jul 21;268(5617):254–257. doi: 10.1038/268254a0. [DOI] [PubMed] [Google Scholar]
  34. Schimmel M., Utiger R. D. Thyroidal and peripheral production of thyroid hormones. Review of recent findings and their clinical implications. Ann Intern Med. 1977 Dec;87(6):760–768. doi: 10.7326/0003-4819-87-6-760. [DOI] [PubMed] [Google Scholar]
  35. Spector D. A., Davis P. J., Helderman J. H., Bell B., Utiger R. D. Thyroid function and metabolic state in chronic renal failure. Ann Intern Med. 1976 Dec;85(6):724–730. doi: 10.7326/0003-4819-85-6-724. [DOI] [PubMed] [Google Scholar]
  36. Surks M. I., Grajower M. M., Tai M., DeFesi C. R. Decreased hepatic nuclear L-triiodothyronine receptors in rats and mice bearing transplantable neoplasms. Endocrinology. 1978 Dec;103(6):2234–2239. doi: 10.1210/endo-103-6-2234. [DOI] [PubMed] [Google Scholar]
  37. Surks M. I., Koerner D. H., Oppenheimer J. H. In vitro binding of L-triiodothyronine to receptors in rat liver nuclei. Kinectics of binding, extraction properties, and lack of requirement for cytosol proteins. J Clin Invest. 1975 Jan;55(1):50–60. doi: 10.1172/JCI107917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Surks M. I., Oppenheimer J. H. Concentration of L-thyroxine and L-triiodothyronine specifically bound to nuclear receptors in rat liver and kidney. Quantitative evidence favoring a major role of T3 in thyroid hormone action. J Clin Invest. 1977 Sep;60(3):555–562. doi: 10.1172/JCI108807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Surks M. I., Schadlow A. R., Oppenheimer J. H. A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement. J Clin Invest. 1972 Dec;51(12):3104–3113. doi: 10.1172/JCI107137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Towle H. C., Mariash C. N., Oppenheimer J. H. Changes in the hepatic levels of messenger ribonucleic acid for malic enzyme during induction by thyroid hormone or diet. Biochemistry. 1980 Feb 5;19(3):579–585. doi: 10.1021/bi00544a029. [DOI] [PubMed] [Google Scholar]
  41. Walfish P. G., Orrego H., Israel Y., Blake J., Kalant H. Serum triiodothyronine and other clinical and laboratory indices of alcoholic liver disease. Ann Intern Med. 1979 Jul;91(1):13–16. doi: 10.7326/0003-4819-91-1-13. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES