Advertisement

Regulation of hepatic lipoprotein biosynthesis by hormones

  • W. Patsch
  • W. Strobl
  • N. Gorder
  • Y. C. Lin-Lee
  • A. M. GottoJr
  • J. R. Patsch

Abstract

To identify key regulatory processes of hepatic lipoprotein production, we studied the effects of hormonal perturbations on lipoprotein biosynthesis in the rat. Insulin administration to cultured hepatocytes inhibits the secretion of triglycerides, and apolipoproteins B and E, but does not alter secretory rates of apoproteins A-I and C-III. Net synthesis of apoB and E is not reduced by the hormone, but the rate of transport of apoB from the endoplasmic reticulum to the Golgi is diminished, and the association of apoB with triglyceride declines, resulting in reduced formation of nascent VLDL. Thus, intracellular transport of individual apoproteins is a specific process that can be selectively regulated by physiologic stimuli and that can affect net hepatic lipoprotein production. Thyroid hormones enhance hepatic net production of apoA-I in the rat. Twenty minutes after injection of a receptor saturating dose of T3 into euthyroid rats, apoA-I gene transcription increases, reaches a maximum of 179% of control at 3.5 hours, and remains elevated for 48 hours. Levels of nuclear and cytoplasmic apoA-I mRNA increase at 1 hour and 2 hours, respectively, and exceed the levels expected from enhanced transcription more than twofold at 24 h. Daily administration of 35 ug T3/1OO g body weight s.c. for 1 week increases the abundance of nuclear and cytoplasmic apoA-I mRNA more than threefold, but reduces the transcription of the apoA-I gene to 42% of control injected animals. Thus, thyorid hormone rapidly stimulates apoA-I gene transcription, but posttranscriptional events enhancing the stability of nuclear apoA-I RNA contribute to the acute effect of T3 on apoA-I mRNA levels. In chronic hyperthyroidism, stabilization of nuclear apoA-I RNA precursors is the principal mechanism for enhanced apoA-I gene expression and may cause feedback inhibition of apoA-I gene transcription. Our studies also imply that in euthyroid rats the majority of nuclear apoA-I mRNA precursors is degraded.

Keywords

Hepatocyte Culture mRNA Precursor Vesicular Stomatitis Viral Glycoprotein Albumin mRNA Hepatic Lipoprotein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Patsch, W., Franz, S., and Schonfeld, G. (1983) ‘Role of insulin in lipoprotein secretion by cultured rat hepatocytes’, J. Clin. Invest. 71, 1161–1174.PubMedCrossRefGoogle Scholar
  2. 2.
    Heimberg, M., Olubadewo, J.O., and Wilcox, H.G. (1985) ‘Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states’, Endocrine Reviews 6, 590–607.Google Scholar
  3. 3.
    Wilcox, H.G., Keyes, W.G., Hale, T.A., Frank, R., Morgan, D.W.,and Heimberg, M. (1982) ‘Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats’, J. Lipid Res. 23, 1159–1166.PubMedGoogle Scholar
  4. 4.
    Apostolopoulos, J.J., Howlett, G.J., and Fidge, N. (1987) ‘Effects of dietary cholesterol and hypothyroidism on rat apolipoprotein YRNA metabolism’, J. Lipid Res. 28, 642–648.PubMedGoogle Scholar
  5. 5.
    Yedgar, S., Weinstein, D.B., Patsch, W., Schonfeld, G., Casanada, F.E., and Steinberg, D. (1982) ‘Viscosity of culture media as a regulator of synthesis and secretion of very low density lipoproteins by cultured hepatocytes’, J. Biol. Chem. 257, 2188–2192.PubMedGoogle Scholar
  6. 6.
    Patsch, W., Tamai, T., and Schonfeld, G. (1983) ‘Effect of fatty acids on lipid and apoprotein secretion and association in hepatocyte cultures’, J. Clin. Invest. 72, 371–378.CrossRefGoogle Scholar
  7. 7.
    Weber, K., and Osborn, M. (1969) ‘The reliability of molecular weight determinations by dodecyl sulfate-Polyacrylamide gel electrophoresis’, J. Biol. Chem. 244, 4406–4412.PubMedGoogle Scholar
  8. 8.
    Rothman, J.E., and Fries, E. (1981) ‘Transport of newly synthesized vesicular stomatitis viral glycoprotein to purified Golgi membranes’, J. Cell Biol. 89, 162–168.PubMedCrossRefGoogle Scholar
  9. 9.
    Aronson, N.N., Jr., and Touster, O. (1974) ‘Isolation of rat liver plasma membrane fragments in isotonic sucrose’, Methods Enzymol. 31, 90–102.PubMedCrossRefGoogle Scholar
  10. 10.
    Lin-Lee, Y.C., Kao, F.T., Cheung, P., and Chan, L. (1985) ‘Apolipoprotein E gene mapping and expression: localization of the structural gene to human chromosome 19 and expression of apoE mRA in lipoprotein and non-lipoprotein-producing tissues’, Biochemistry 24, 3751–3756.PubMedCrossRefGoogle Scholar
  11. 11.
    Thomas, P. (1980) ‘Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose’, Proc. Natl. Acad. Sci. USA 77, 5201–5205.PubMedCrossRefGoogle Scholar
  12. 12.
    Northemann, W., Heisig, M., Kunz, D., and Heinrich, P.C. (1985) ‘Molecular cloning of cDNA sequences for rat alpha2-macroglobulin and measurement of its transcription during experimental inflammation’, J. Biol. Chem. 260, 6200–6205.PubMedGoogle Scholar
  13. 13.
    Kapuscinski, J., and Skoczylas, B. (1977) ‘Simple and rapid fluorimetric method for DNA microassay’, Anal. Biochem. 83, 252–257.PubMedCrossRefGoogle Scholar
  14. 14.
    Birch, H.E., and Schreiber, G. (1986) ‘Transcriptional regulation of plasma protein synthesis during inflanmation’, J. Biol. Chem. 261, 8077–8080.PubMedGoogle Scholar
  15. 15.
    Strobl, W., Gorder, N.L., Fienup, G.A., Lin-Lee, Y.C., Gotto, A.M.,Jr., and Patsch, W. (1989) ‘Effect of sucrose diet on apolipoprotein biosynthesis in rat liver: increase in apolipoprotein E gene transcription’, J. Biol. Chem. 264, 1190–1194.PubMedGoogle Scholar
  16. 16.
    Roop, d.R., Nordstrom, J.L., Tsai, S., Tsai, M.J., and O’Malley, B.W.(1978) ’Transcription of structural and intervening sequences in the ovalbumin gene and identification of potential ovalbumin mRNA precursors. Cell 15, 671–685.PubMedCrossRefGoogle Scholar
  17. 17.
    Lamers, W.H., Hanson, R.W., and Meisner, H.M. (1982) ‘cAMP stimulates transcription of the gene for cytosolic phosphoenolpyruvate corboxykinase in rat liver nuclei’, Proc. Natl. Acad. Sci. USA 79, 5137–5141.PubMedCrossRefGoogle Scholar
  18. 18.
    Patsch, W., Gotto, A.M., Jr., and Patsch, J.R. (1986) ‘Effects of insulin on lipoprotein secretion in rat hepatocyte cultures: the role of the insulin receptor’, J. Biol. Chem. 261, 9603–9606.PubMedGoogle Scholar
  19. 19.
    Patsch, W., Lin-Lee, Y.C., Gotto, A.M., Jr., and Patsch, J.R. (1986) ‘Hepatic lipoprotein biogenesis: the role of intracellular apolipoprotein transport’, Arteriosclerosis 6, 536a.Google Scholar
  20. 20.
    Strobl, W., Gorder, N., Lin-Lee, Y.C., Fienup, G., Gotto, A.M.,Jr., and Patsch, W. (1989) ‘The role of thyroid hormone in hepatic Apolipoprotein A-1 gene expression in the rat’ Clin. Res. 37, 300a.Google Scholar
  21. 21.
    Samuels, H.H., Forman, B.M., Horowitz, Z.D., and Ye, Z.-S. (1988) ‘Regulation of gene expression by thyroid hormone’, J. Clin. Invest. 81, 957–967.PubMedCrossRefGoogle Scholar
  22. 22.
    Nyborg, J.K., Nguyen, A.P., and Spindler, S.R. (1984) ‘Relationship between thyroid and glucocortiod hormone receptor occupancy, growth hormone gene transcription, and mRNA accumulation’ J. Biol. Chem. 259, 12377–12381.PubMedGoogle Scholar
  23. 23.
    Glass, C.K., Franco, R., Weinberger, C., Albert, V., Evans, R., and Rosenfeld, M.G. (1987) ’A c-erb-A binding site in rat growth hormone gene mediates trans-activation by thyroid hormone. Nature 329, 738–741.PubMedCrossRefGoogle Scholar
  24. 24.
    Narayan, P., and Towle, H.C. (1985) ‘Stabilization of a specific nuclear mRNA precursor by thyroid hormone’ Mol. Cell. Biol. 5, 2642–2646.PubMedGoogle Scholar
  25. 25.
    Davidson, N.O., Powell, L.M., Wallis, S.C., and Scott, J. (1988) ‘Thyroid hormone modulates the introduction of a stop codon in rat liver apolipoprotein B messenger RNA’ J. Biol. Chem. 263, 13482–13485.Google Scholar

Copyright information

© Kluwer Academic Publishers 1990

Authors and Affiliations

  • W. Patsch
    • 1
  • W. Strobl
    • 1
  • N. Gorder
    • 1
  • Y. C. Lin-Lee
    • 1
  • A. M. GottoJr
    • 1
  • J. R. Patsch
    • 1
  1. 1.Baylor College of MedicineHoustonUSA

Personalised recommendations