Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1981 Nov;68(5):1197–1206. doi: 10.1172/JCI110365

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

R W Mahley, D Y Hui, T L Innerarity, K H Weisgraber
PMCID: PMC370914  PMID: 6271808

Abstract

We have reported previously that canine livers possess two distinct lipoprotein receptors, an apoprotein (apo)-B,E receptor capable of binding the apo-B-containing low density lipoproteins (LDL) and the apo-E-containing cholesterol-induced high density lipoproteins (HDLc), and an apo-E receptor capable of binding apo-E HDLc but not LDL. Both the apo-B,E and apo-E receptors were found on the liver membranes obtained from immature growing dogs, but only the apo-E receptors were detected on th hepatic membranes of adult dogs. In this study, the expression of the apo-B,E receptors, as determined by canine LDL binding to the hepatic membranes, was found to be highly dependent on the age of the dog and decreased linearly with increasing age. Approximately 30 ng of LDL protein per milligram of membrane protein were bound via the apo-B,E receptors to the hepatic membranes of 7- to 8-wk-old immature dogs as compared with no detectable LDL binding in the hepatic membranes of adult dogs (greater than 1--1.5 yr of age). Results obtained by in vivo turnover studies of canine 125I-LDL correlated with the in vitro findings. In addition to a decrease in the expression of the hepatic apo-B,E receptors with age, these receptors were regulated, i.e., cholesterol feeding suppressed these receptors in immature dogs and prolonged fasting induced their expression in adult dogs. Previously, it was shown that the apo-B,E receptors were induced in adult livers following treatment with the hypocholesterolemic drug cholestyramine. In striking contrast, the apo-E receptors, as determined by apo-E HDLc binding, remained relatively constant for all ages of dogs studied (10--12 ng/mg). Moreover, the expression of the apo-E receptors was not strictly regulated by the metabolic perturbations that regulated the apo-B,E receptors. Similar results concerning the presence of apo-B,E and apo-E receptors were obtained in swine and in man. The hepatic membranes of adult swine bound only apo-E HDLc (apo-E receptors), whereas the membranes from fetal swine livers bound both LDL and apo-E HDLc (apo B,E and apo-E receptors). Furthermore, the membranes from adult human liver revealed the presence of the apo-E receptors as evidenced by the binding of 12--14 ng of HDLc protein per milligram of membrane protein and less than 1 ng of LDL protein per milligram. The membranes from the human liver also bound human chylomicron remnants and a subfraction of human HDL containing apo-E. These data suggest the importance of the E apoprotein and the apo-E receptors in mediating lipoprotein clearance, including chylomicron remnants, by the liver of adult dogs, swine, and man.

Full text

PDF
1197

Selected References

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

  1. Ahlberg J., Angelin B., Björkhem I., Einarsson K., Leijd B. Hepatic cholesterol metabolism in normo- and hyperlipidemic patients with cholesterol gallstones. J Lipid Res. 1979 Jan;20(1):107–115. [PubMed] [Google Scholar]
  2. Basu S. K., Goldstein J. L., Brown M. S. Characterization of the low density lipoprotein receptor in membranes prepared from human fibroblasts. J Biol Chem. 1978 Jun 10;253(11):3852–3856. [PubMed] [Google Scholar]
  3. Beisiegel U., Kita T., Anderson R. G., Schneider W. J., Brown M. S., Goldstein J. L. Immunologic cross-reactivity of the low density lipoprotein receptor from bovine adrenal cortex, human fibroblasts, canine liver and adrenal gland, and rat liver. J Biol Chem. 1981 Apr 25;256(8):4071–4078. [PubMed] [Google Scholar]
  4. Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
  5. Brown M. S., Kovanen P. T., Goldstein J. L. Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog Horm Res. 1979;35:215–257. doi: 10.1016/b978-0-12-571135-7.50009-6. [DOI] [PubMed] [Google Scholar]
  6. Dietschy J. M., Wilson J. D. Regulation of cholesterol metabolism. I. N Engl J Med. 1970 May 14;282(20):1128–1138. doi: 10.1056/NEJM197005142822005. [DOI] [PubMed] [Google Scholar]
  7. Florén C. H., Albers J. J., Kudchodkar B. J., Bierman E. L. Receptor-dependent uptake of human chylomicron remnants by cultured skin fibroblasts. J Biol Chem. 1981 Jan 10;256(1):425–433. [PubMed] [Google Scholar]
  8. Hui D. Y., Innerarity T. L., Mahley R. W. Lipoprotein binding to canine hepatic membranes. Metabolically distinct apo-E and apo-B,E receptors. J Biol Chem. 1981 Jun 10;256(11):5646–5655. [PubMed] [Google Scholar]
  9. Innerarity T. L., Mahley R. W. Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins. Biochemistry. 1978 Apr 18;17(8):1440–1447. doi: 10.1021/bi00601a013. [DOI] [PubMed] [Google Scholar]
  10. Innerarity T. L., Mahley R. W., Weisgraber K. H., Bersot T. P. Apoprotein (E--A-II) complex of human plasma lipoproteins. II. Receptor binding activity of a high density lipoprotein subfraction modulated by the apo(E--A-II) complex. J Biol Chem. 1978 Sep 10;253(17):6289–6295. [PubMed] [Google Scholar]
  11. Innerarity T. L., Pitas R. E., Mahley R. W. Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts. J Biol Chem. 1979 May 25;254(10):4186–4190. [PubMed] [Google Scholar]
  12. Kovanen P. T., Basu S. K., Goldstein J. L., Brown M. S. Low density lipoprotein receptors in bovine adrenal cortex. II. Low density lipoprotein binding to membranes prepared from fresh tissue. Endocrinology. 1979 Mar;104(3):610–616. doi: 10.1210/endo-104-3-610. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Kovanen P. T., Brown M. S., Basu S. K., Bilheimer D. W., Goldstein J. L. Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1396–1400. doi: 10.1073/pnas.78.3.1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. MATTHEWS C. M. The theory of tracer experiments with 131I-labelled plasma proteins. Phys Med Biol. 1957 Jul;2(1):36–53. doi: 10.1088/0031-9155/2/1/305. [DOI] [PubMed] [Google Scholar]
  17. Mahley R. W., Innerarity T. L., Weisgraber K. B., Oh S. Y. Altered metabolism (in vivo and in vitro) of plasma lipoproteins after selective chemical modification of lysine residues of the apoproteins. J Clin Invest. 1979 Sep;64(3):743–750. doi: 10.1172/JCI109518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mahley R. W., Innerarity T. L., Weisgraber K. H., Fry D. L. Canine hyperlipoproteinemia and atherosclerosis. Accumulation of lipid by aortic medial cells in vivo and in vitro. Am J Pathol. 1977 Apr;87(1):205–226. [PMC free article] [PubMed] [Google Scholar]
  19. Mahley R. W., Weisgraber K. H. Canine lipoproteins and atherosclerosis. I. Isolation and characterization of plasma lipoproteins from control dogs. Circ Res. 1974 Nov;35(5):713–721. doi: 10.1161/01.res.35.5.713. [DOI] [PubMed] [Google Scholar]
  20. Pertsemlidis D., Kirchman E. H., Ahrens E. H., Jr Regulation of cholesterol metabolism in the dog. I. Effects of complete bile diversion and of cholesterol feeding on absorption, synthesis, accumulation, and excretion rates measured during life. J Clin Invest. 1973 Sep;52(9):2353–2367. doi: 10.1172/JCI107424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pitas R. E., Innerarity T. L., Arnold K. S., Mahley R. W. Rate and equilibrium constants for binding of apo-E HDLc (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: evidence for multiple receptor binding of apo-E HDLc. Proc Natl Acad Sci U S A. 1979 May;76(5):2311–2315. doi: 10.1073/pnas.76.5.2311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Quarfordt S. H., Shelburne F. A., Meyers W., Jakoi L., Hanks J. Effect of apolipoproteins on the induction of hepatic steatosis in rats. Gastroenterology. 1981 Jan;80(1):149–153. [PubMed] [Google Scholar]
  23. Shelburne F., Hanks J., Meyers W., Quarfordt S. Effect of apoproteins on hepatic uptake of triglyceride emulsions in the rat. J Clin Invest. 1980 Mar;65(3):652–658. doi: 10.1172/JCI109710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sherrill B. C., Innerarity T. L., Mahley R. W. Rapid hepatic clearance of the canine lipoproteins containing only the E apoprotein by a high affinity receptor. Identity with the chylomicron remnant transport process. J Biol Chem. 1980 Mar 10;255(5):1804–1807. [PubMed] [Google Scholar]
  25. WOJCIECH R., JANECEK H. M., IVY A. C. Endogenous excretion and intestinal capacity for absorption of cholesterol in the dog. Am J Physiol. 1961 Jul;201:190–193. doi: 10.1152/ajplegacy.1961.201.1.190. [DOI] [PubMed] [Google Scholar]
  26. Weisgraber K. H., Mahley R. W. Subfractionation of human high density lipoproteins by heparin-Sepharose affinity chromatography. J Lipid Res. 1980 Mar;21(3):316–325. [PubMed] [Google Scholar]
  27. Windler E., Chao Y., Havel R. J. Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apoproteins. J Biol Chem. 1980 Sep 10;255(17):8303–8307. [PubMed] [Google Scholar]

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

RESOURCES