Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jan 15;97(2):292–299. doi: 10.1172/JCI118415

Regulation of rat hepatic low density lipoprotein receptors. In vivo stimulation by growth hormone is not mediated by insulin-like growth factor I.

M Rudling 1, H Olivecrona 1, G Eggertsen 1, B Angelin 1
PMCID: PMC507017  PMID: 8567947

Abstract

Growth hormone (GH) has an important role in the regulation of hepatic LDL receptor expression and plasma lipoprotein levels. This investigation was undertaken to evaluate if these effects of GH on hepatic LDL receptors are direct or mediated by insulin-like growth factor I (IGF-I). Two models were studied in which substitution with GH is important for the regulation of hepatic LDL receptors: hypophysectomized rats receiving high-dose ethynylestradiol or challenge with dietary cholesterol. The hypophysectomized rats were hormonally substituted by infusion with dexamethasone and L-thyroxine, and either GH or IGF-I. In both models, GH was essential for maintaining normal expression of LDL receptors. In contrast, despite fully normalized plasma levels, IGF-I did not support the expression of hepatic LDL receptors. Analysis of plasma lipoproteins revealed that substitution with GH, but not with IGF-I, reduced LDL and intermediate density lipoproteins. In addition, determination of hepatic mRNA levels for apo B-100 and apo B-48 indicated that GH may be more effective than IGF-I in the promotion of apo B mRNA editing. In conclusion, GH has specific effects on hepatic LDL receptor expression and plasma lipoprotein levels that are not mediated by IGF-I.

Full Text

The Full Text of this article is available as a PDF (273.9 KB).

Selected References

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

  1. Akerlund J. E., Reihnér E., Angelin B., Rudling M., Ewerth S., Björkhem I., Einarsson K. Hepatic metabolism of cholesterol in Crohn's disease. Effect of partial resection of ileum. Gastroenterology. 1991 Apr;100(4):1046–1053. doi: 10.1016/0016-5085(91)90281-o. [DOI] [PubMed] [Google Scholar]
  2. Angelin B. 1994 Mack-Forster Award Lecture. Review. Studies on the regulation of hepatic cholesterol metabolism in humans. Eur J Clin Invest. 1995 Apr;25(4):215–224. doi: 10.1111/j.1365-2362.1995.tb01552.x. [DOI] [PubMed] [Google Scholar]
  3. Angelin B., Olivecrona H., Reihnér E., Rudling M., Ståhlberg D., Eriksson M., Ewerth S., Henriksson P., Einarsson K. Hepatic cholesterol metabolism in estrogen-treated men. Gastroenterology. 1992 Nov;103(5):1657–1663. doi: 10.1016/0016-5085(92)91192-7. [DOI] [PubMed] [Google Scholar]
  4. Angelin B., Rudling M. Growth hormone and hepatic lipoprotein metabolism. Curr Opin Lipidol. 1994 Jun;5(3):160–165. doi: 10.1097/00041433-199405030-00002. [DOI] [PubMed] [Google Scholar]
  5. Baum C. L., Teng B. B., Davidson N. O. Apolipoprotein B messenger RNA editing in the rat liver. Modulation by fasting and refeeding a high carbohydrate diet. J Biol Chem. 1990 Nov 5;265(31):19263–19270. [PubMed] [Google Scholar]
  6. Brindley D. N., Salter A. M. Hormonal regulation of the hepatic low density lipoprotein receptor and the catabolism of low density lipoproteins: relationship with the secretion of very low density lipoproteins. Prog Lipid Res. 1991;30(4):349–360. doi: 10.1016/0163-7827(91)90003-n. [DOI] [PubMed] [Google Scholar]
  7. Brown G., Albers J. J., Fisher L. D., Schaefer S. M., Lin J. T., Kaplan C., Zhao X. Q., Bisson B. D., Fitzpatrick V. F., Dodge H. T. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990 Nov 8;323(19):1289–1298. doi: 10.1056/NEJM199011083231901. [DOI] [PubMed] [Google Scholar]
  8. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  9. Buchwald H., Varco R. L., Matts J. P., Long J. M., Fitch L. L., Campbell G. S., Pearce M. B., Yellin A. E., Edmiston W. A., Smink R. D., Jr Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH) N Engl J Med. 1990 Oct 4;323(14):946–955. doi: 10.1056/NEJM199010043231404. [DOI] [PubMed] [Google Scholar]
  10. Caro J. F., Poulos J., Ittoop O., Pories W. J., Flickinger E. G., Sinha M. K. Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest. 1988 Apr;81(4):976–981. doi: 10.1172/JCI113451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daughaday W. H., Mariz I. K., Blethen S. L. Inhibition of access of bound somatomedin to membrane receptor and immunobinding sites: a comparison of radioreceptor and radioimmunoassay of somatomedin in native and acid-ethanol-extracted serum. J Clin Endocrinol Metab. 1980 Oct;51(4):781–788. doi: 10.1210/jcem-51-4-781. [DOI] [PubMed] [Google Scholar]
  12. Dietschy J. M., Turley S. D., Spady D. K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993 Oct;34(10):1637–1659. [PubMed] [Google Scholar]
  13. Elam M. B., Simkevich C. P., Solomon S. S., Wilcox H. G., Heimberg M. Stimulation of in vitro triglyceride synthesis in the rat hepatocyte by growth hormone treatment in vivo. Endocrinology. 1988 Apr;122(4):1397–1402. doi: 10.1210/endo-122-4-1397. [DOI] [PubMed] [Google Scholar]
  14. Elam M. B., Wilcox H. G., Solomon S. S., Heimberg M. In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver. Endocrinology. 1992 Dec;131(6):2717–2722. doi: 10.1210/endo.131.6.1446613. [DOI] [PubMed] [Google Scholar]
  15. Ericsson S., Eriksson M., Vitols S., Einarsson K., Berglund L., Angelin B. Influence of age on the metabolism of plasma low density lipoproteins in healthy males. J Clin Invest. 1991 Feb;87(2):591–596. doi: 10.1172/JCI115034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Frick M. H., Elo O., Haapa K., Heinonen O. P., Heinsalmi P., Helo P., Huttunen J. K., Kaitaniemi P., Koskinen P., Manninen V. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987 Nov 12;317(20):1237–1245. doi: 10.1056/NEJM198711123172001. [DOI] [PubMed] [Google Scholar]
  17. Goldstein J. L., Brown M. S. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425–430. doi: 10.1038/343425a0. [DOI] [PubMed] [Google Scholar]
  18. Gordon T., Kannel W. B., Castelli W. P., Dawber T. R. Lipoproteins, cardiovascular disease, and death. The Framingham study. Arch Intern Med. 1981 Aug;141(9):1128–1131. [PubMed] [Google Scholar]
  19. Hochberg Z., Hertz P., Maor G., Oiknine J., Aviram M. Growth hormone and insulin-like growth factor-I increase macrophage uptake and degradation of low density lipoprotein. Endocrinology. 1992 Jul;131(1):430–435. doi: 10.1210/endo.131.1.1612024. [DOI] [PubMed] [Google Scholar]
  20. Inui Y., Giannoni F., Funahashi T., Davidson N. O. REPR and complementation factor(s) interact to modulate rat apolipoprotein B mRNA editing in response to alterations in cellular cholesterol flux. J Lipid Res. 1994 Aug;35(8):1477–1489. [PubMed] [Google Scholar]
  21. Kovanen P. T., Bilheimer D. W., Goldstein J. L., Jaramillo J. J., Brown M. S. Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1194–1198. doi: 10.1073/pnas.78.2.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kovanen P. T., Brown M. S., Goldstein J. L. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11367–11373. [PubMed] [Google Scholar]
  23. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  24. Olivecrona H., Johansson A. G., Lindh E., Ljunghall S., Berglund L., Angelin B. Hormonal regulation of serum lipoprotein(a) levels. Contrasting effects of growth hormone and insulin-like growth factor-I. Arterioscler Thromb Vasc Biol. 1995 Jul;15(7):847–849. doi: 10.1161/01.atv.15.7.847. [DOI] [PubMed] [Google Scholar]
  25. Parini P., Angelin B., Lobie P. E., Norstedt G., Rudling M. Growth hormone specifically stimulates the expression of low density lipoprotein receptors in human hepatoma cells. Endocrinology. 1995 Sep;136(9):3767–3773. doi: 10.1210/endo.136.9.7649083. [DOI] [PubMed] [Google Scholar]
  26. Reihnér E., Rudling M., Ståhlberg D., Berglund L., Ewerth S., Björkhem I., Einarsson K., Angelin B. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med. 1990 Jul 26;323(4):224–228. doi: 10.1056/NEJM199007263230403. [DOI] [PubMed] [Google Scholar]
  27. Rudling M. J., Reihnér E., Einarsson K., Ewerth S., Angelin B. Low density lipoprotein receptor-binding activity in human tissues: quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo. Proc Natl Acad Sci U S A. 1990 May;87(9):3469–3473. doi: 10.1073/pnas.87.9.3469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rudling M. J. Role of the liver for the receptor-mediated catabolism of low-density lipoprotein in the 17 alpha-ethinylestradiol-treated rat. Biochim Biophys Acta. 1987 Jun 2;919(2):175–180. doi: 10.1016/0005-2760(87)90205-0. [DOI] [PubMed] [Google Scholar]
  29. Rudling M., Angelin B. Loss of resistance to dietary cholesterol in the rat after hypophysectomy: importance of the presence of growth hormone for hepatic low density lipoprotein-receptor expression. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8851–8855. doi: 10.1073/pnas.90.19.8851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rudling M., Angelin B. Stimulation of rat hepatic low density lipoprotein receptors by glucagon. Evidence of a novel regulatory mechanism in vivo. J Clin Invest. 1993 Jun;91(6):2796–2805. doi: 10.1172/JCI116522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rudling M. Hepatic mRNA levels for the LDL receptor and HMG-CoA reductase show coordinate regulation in vivo. J Lipid Res. 1992 Apr;33(4):493–501. [PubMed] [Google Scholar]
  32. Rudling M., Norstedt G., Olivecrona H., Reihnér E., Gustafsson J. A., Angelin B. Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6983–6987. doi: 10.1073/pnas.89.15.6983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Salter A. M., Hayashi R., al-Seeni M., Brown N. F., Bruce J., Sorensen O., Atkinson E. A., Middleton B., Bleackley R. C., Brindley D. N. Effects of hypothyroidism and high-fat feeding on mRNA concentrations for the low-density-lipoprotein receptor and on acyl-CoA:cholesterol acyltransferase activities in rat liver. Biochem J. 1991 Jun 15;276(Pt 3):825–832. doi: 10.1042/bj2760825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sjöberg A., Oscarsson J., Boström K., Innerarity T. L., Edén S., Olofsson S. O. Effects of growth hormone on apolipoprotein-B (apoB) messenger ribonucleic acid editing, and apoB 48 and apoB 100 synthesis and secretion in the rat liver. Endocrinology. 1992 Jun;130(6):3356–3364. doi: 10.1210/endo.130.6.1597147. [DOI] [PubMed] [Google Scholar]
  35. Sjöberg A., Oscarsson J., Edén S., Olofsson S. O. Continuous but not intermittent administration of growth hormone to hypophysectomized rats increases apolipoprotein-E secretion from cultured hepatocytes. Endocrinology. 1994 Feb;134(2):790–798. doi: 10.1210/endo.134.2.8299573. [DOI] [PubMed] [Google Scholar]
  36. Sjöberg A., Oscarsson J., Olofsson S. O., Edén S. Insulin-like growth factor-I and growth hormone have different effects on serum lipoproteins and secretion of lipoproteins from cultured rat hepatocytes. Endocrinology. 1994 Oct;135(4):1415–1421. doi: 10.1210/endo.135.4.7925103. [DOI] [PubMed] [Google Scholar]
  37. Sparks C. E., Marsh J. B. Metabolic heterogeneity of apolipoprotein B in the rat. J Lipid Res. 1981 Mar;22(3):519–527. [PubMed] [Google Scholar]
  38. Srivastava R. A., Tang J., Baumann D., Schonfeld G. Hormonal and nutritional stimuli modulate apolipoprotein B mRNA editing in mouse liver. Biochem Biophys Res Commun. 1992 Oct 15;188(1):135–141. doi: 10.1016/0006-291x(92)92360-a. [DOI] [PubMed] [Google Scholar]
  39. Tamura K., Kobayashi M., Ishii Y., Tamura T., Hashimoto K., Nakamura S., Niwa M., Zapf J. Primary structure of rat insulin-like growth factor-I and its biological activities. J Biol Chem. 1989 Apr 5;264(10):5616–5621. [PubMed] [Google Scholar]
  40. Veldhuis J. D., Nestler J. E., Strauss J. F., 3rd The insulin-like growth factor, somatomedin-C, modulates low density lipoprotein metabolism by swine granulosa cells. Endocrinology. 1987 Jul;121(1):340–346. doi: 10.1210/endo-121-1-340. [DOI] [PubMed] [Google Scholar]
  41. Vikman-Adolfsson K., Oscarsson J., Nilsson-Ehle P., Edén S. Growth hormone but not gonadal steroids influence lipoprotein lipase and hepatic lipase activity in hypophysectomized rats. J Endocrinol. 1994 Feb;140(2):203–209. doi: 10.1677/joe.0.1400203. [DOI] [PubMed] [Google Scholar]
  42. Wade D. P., Knight B. L., Soutar A. K. Regulation of low-density-lipoprotein-receptor mRNA by insulin in human hepatoma Hep G2 cells. Eur J Biochem. 1989 May 15;181(3):727–731. doi: 10.1111/j.1432-1033.1989.tb14784.x. [DOI] [PubMed] [Google Scholar]
  43. Zenobi P. D., Jaeggi-Groisman S. E., Riesen W. F., Røder M. E., Froesch E. R. Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest. 1992 Dec;90(6):2234–2241. doi: 10.1172/JCI116109. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES