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. 1995 Mar;95(3):1124–1132. doi: 10.1172/JCI117760

Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.

Y Osono 1, L A Woollett 1, J Herz 1, J M Dietschy 1
PMCID: PMC441449  PMID: 7883961

Abstract

These studies were undertaken to quantify cholesterol balance across the plasma space and the individual organs of the mouse, and to determine the role of the low density lipoprotein receptor (LDLR) in these two processes. In the normal mouse (129 Sv), sterol was synthesized at the rate of 153 mg/d per kg body weight of which 78% occurred in the extrahepatic tissues while only 22% took place in the liver. These animals metabolized 7.1 pools of LDL-cholesterol (LDL-C) per day, and 79% of this degradation took place in the liver. Of this total turnover, the LDLR accounted for 88% while the remaining 12% was receptor independent. 91% of the receptor-dependent transport identified in these animals was located in the liver while only 38% of the receptor-independent uptake wsa found in this organ. When the LDLR was deleted, the LDL-C production rate increased 1.7-fold, LDL-C turnover decreased from 7.1 to 0.88 pools/d, and the plasma LDL-C level increased 14-fold, from 7 to 101 mg/dl. Despite these major changes in the circulating levels of LDL-C, however, there was no change in the rate of cholesterol synthesis in any extrahepatic organ or in the whole animal, and, further, there was no change in the steady-state cholesterol concentration in any organ. Thus, most extrahepatic tissues synthesize their daily sterol requirements while most LDL-C is returned directly to the liver. Changes in LDLR activity, therefore, profoundly alter the plasma LDL-C concentration but have virtually no affect on cholesterol balance across any extrahepatic organ, including the brain.

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Selected References

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  1. Andersen J. M., Dietschy J. M. Relative importance of high and low density lipoproteins in the regulation of cholesterol synthesis in the adrenal gland, ovary, and testis of the rat. J Biol Chem. 1978 Dec 25;253(24):9024–9032. [PubMed] [Google Scholar]
  2. Beisiegel U., Weber W., Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8342–8346. doi: 10.1073/pnas.88.19.8342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bilheimer D. W., Goldstein J. L., Grundy S. M., Starzl T. E., Brown M. S. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med. 1984 Dec 27;311(26):1658–1664. doi: 10.1056/NEJM198412273112603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bilheimer D. W., Stone N. J., Grundy S. M. Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo. J Clin Invest. 1979 Aug;64(2):524–533. doi: 10.1172/JCI109490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bill A., Herbai G., Westman-Naeser S. Red blood cell and plasma volumes, total body water and sulfate space in obese-hyperglycemic mice and lean litter mates. Acta Physiol Scand. 1971 Aug;82(4):470–476. doi: 10.1111/j.1748-1716.1971.tb04992.x. [DOI] [PubMed] [Google Scholar]
  6. Chan L. Apolipoprotein B, the major protein component of triglyceride-rich and low density lipoproteins. J Biol Chem. 1992 Dec 25;267(36):25621–25624. [PubMed] [Google Scholar]
  7. Chen Z., Peto R., Collins R., MacMahon S., Lu J., Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991 Aug 3;303(6797):276–282. doi: 10.1136/bmj.303.6797.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Daumerie C. M., Woollett L. A., Dietschy J. M. Fatty acids regulate hepatic low density lipoprotein receptor activity through redistribution of intracellular cholesterol pools. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10797–10801. doi: 10.1073/pnas.89.22.10797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Demmer L. A., Levin M. S., Elovson J., Reuben M. A., Lusis A. J., Gordon J. I. Tissue-specific expression and developmental regulation of the rat apolipoprotein B gene. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8102–8106. doi: 10.1073/pnas.83.21.8102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dietschy J. M., Kita T., Suckling K. E., Goldstein J. L., Brown M. S. Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors. J Lipid Res. 1983 Apr;24(4):469–480. [PubMed] [Google Scholar]
  11. Dietschy J. M., Spady D. K. Measurement of rates of cholesterol synthesis using tritiated water. J Lipid Res. 1984 Dec 15;25(13):1469–1476. [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. Elovson J., Huang Y. O., Baker N., Kannan R. Apolipoprotein B is structurally and metabolically heterogeneous in the rat. Proc Natl Acad Sci U S A. 1981 Jan;78(1):157–161. doi: 10.1073/pnas.78.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Glass C. K., Pittman R. C., Keller G. A., Steinberg D. Tissue sites of degradation of apoprotein A-I in the rat. J Biol Chem. 1983 Jun 10;258(11):7161–7167. [PubMed] [Google Scholar]
  15. Havel R. J. Functional activities of hepatic lipoprotein receptors. Annu Rev Physiol. 1986;48:119–134. doi: 10.1146/annurev.ph.48.030186.001003. [DOI] [PubMed] [Google Scholar]
  16. Herz J., Hamann U., Rogne S., Myklebost O., Gausepohl H., Stanley K. K. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 1988 Dec 20;7(13):4119–4127. doi: 10.1002/j.1460-2075.1988.tb03306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Higuchi K., Kitagawa K., Kogishi K., Takeda T. Developmental and age-related changes in apolipoprotein B mRNA editing in mice. J Lipid Res. 1992 Dec;33(12):1753–1764. [PubMed] [Google Scholar]
  18. Holme I. An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation. 1990 Dec;82(6):1916–1924. doi: 10.1161/01.cir.82.6.1916. [DOI] [PubMed] [Google Scholar]
  19. Innerarity T. L., Weisgraber K. H., Arnold K. S., Mahley R. W., Krauss R. M., Vega G. L., Grundy S. M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6919–6923. doi: 10.1073/pnas.84.19.6919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Innerarity T. L., Young S. G., Poksay K. S., Mahley R. W., Smith R. S., Milne R. W., Marcel Y. L., Weisgraber K. H. Structural relationship of human apolipoprotein B48 to apolipoprotein B100. J Clin Invest. 1987 Dec;80(6):1794–1798. doi: 10.1172/JCI113273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Johnson W. J., Mahlberg F. H., Rothblat G. H., Phillips M. C. Cholesterol transport between cells and high-density lipoproteins. Biochim Biophys Acta. 1991 Oct 1;1085(3):273–298. doi: 10.1016/0005-2760(91)90132-2. [DOI] [PubMed] [Google Scholar]
  23. Kane J. P. Apolipoprotein B: structural and metabolic heterogeneity. Annu Rev Physiol. 1983;45:637–650. doi: 10.1146/annurev.ph.45.030183.003225. [DOI] [PubMed] [Google Scholar]
  24. Kane J. P., Hardman D. A., Paulus H. E. Heterogeneity of apolipoprotein B: isolation of a new species from human chylomicrons. Proc Natl Acad Sci U S A. 1980 May;77(5):2465–2469. doi: 10.1073/pnas.77.5.2465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kita T., Brown M. S., Bilheimer D. W., Goldstein J. L. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. doi: 10.1073/pnas.79.18.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kita T., Goldstein J. L., Brown M. S., Watanabe Y., Hornick C. A., Havel R. J. Hepatic uptake of chylomicron remnants in WHHL rabbits: a mechanism genetically distinct from the low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3623–3627. doi: 10.1073/pnas.79.11.3623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Kowal R. C., Herz J., Goldstein J. L., Esser V., Brown M. S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. doi: 10.1073/pnas.86.15.5810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kowal R. C., Herz J., Weisgraber K. H., Mahley R. W., Brown M. S., Goldstein J. L. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Jun 25;265(18):10771–10779. [PubMed] [Google Scholar]
  30. Krishnaiah K. V., Walker L. F., Borensztajn J., Schonfeld G., Getz G. S. Apolipoprotein B variant derived from rat intestine. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3806–3810. doi: 10.1073/pnas.77.7.3806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mahley R. W., Innerarity T. L. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta. 1983 May 24;737(2):197–222. doi: 10.1016/0304-4157(83)90001-1. [DOI] [PubMed] [Google Scholar]
  32. Mahley R. W., Weisgraber K. H., Melchior G. W., Innerarity T. L., Holcombe K. S. Inhibition of receptor-mediated clearance of lysine and arginine-modified lipoproteins from the plasma of rats and monkeys. Proc Natl Acad Sci U S A. 1980 Jan;77(1):225–229. doi: 10.1073/pnas.77.1.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Meddings J. B., Dietschy J. M. Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation. 1986 Oct;74(4):805–814. doi: 10.1161/01.cir.74.4.805. [DOI] [PubMed] [Google Scholar]
  34. Miserez A. R., Laager R., Chiodetti N., Keller U. High prevalence of familial defective apolipoprotein B-100 in Switzerland. J Lipid Res. 1994 Apr;35(4):574–583. [PubMed] [Google Scholar]
  35. Rubinsztein D. C., Cohen J. C., Berger G. M., van der Westhuyzen D. R., Coetzee G. A., Gevers W. Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects. J Clin Invest. 1990 Oct;86(4):1306–1312. doi: 10.1172/JCI114839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scott J. The molecular and cell biology of apolipoprotein-B. Mol Biol Med. 1989 Feb;6(1):65–80. [PubMed] [Google Scholar]
  37. Sherrill B. C., Dietschy J. M. Characterization of the sinusoidal transport process responsible for uptake of chylomicrons by the liver. J Biol Chem. 1978 Mar 25;253(6):1859–1867. [PubMed] [Google Scholar]
  38. Spady D. K., Bilheimer D. W., Dietschy J. M. Rates of receptor-dependent and -independent low density lipoprotein uptake in the hamster. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3499–3503. doi: 10.1073/pnas.80.11.3499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Spady D. K., Dietschy J. M. Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4526–4530. doi: 10.1073/pnas.82.13.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Spady D. K., Dietschy J. M. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res. 1983 Mar;24(3):303–315. [PubMed] [Google Scholar]
  41. Spady D. K., Huettinger M., Bilheimer D. W., Dietschy J. M. Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit. J Lipid Res. 1987 Jan;28(1):32–41. [PubMed] [Google Scholar]
  42. Spady D. K., Meddings J. B., Dietschy J. M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster. J Clin Invest. 1986 May;77(5):1474–1481. doi: 10.1172/JCI112460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Spady D. K., Turley S. D., Dietschy J. M. Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences. J Clin Invest. 1985 Sep;76(3):1113–1122. doi: 10.1172/JCI112066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Strickland D. K., Ashcom J. D., Williams S., Burgess W. H., Migliorini M., Argraves W. S. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990 Oct 15;265(29):17401–17404. [PubMed] [Google Scholar]
  45. Turley S. D., Andersen J. M., Dietschy J. M. Rates of sterol synthesis and uptake in the major organs of the rat in vivo. J Lipid Res. 1981 May;22(4):551–569. [PubMed] [Google Scholar]
  46. Turley S. D., Daggy B. P., Dietschy J. M. Psyllium augments the cholesterol-lowering action of cholestyramine in hamsters by enhancing sterol loss from the liver. Gastroenterology. 1994 Aug;107(2):444–452. doi: 10.1016/0016-5085(94)90170-8. [DOI] [PubMed] [Google Scholar]
  47. Vega G. L., Grundy S. M. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest. 1986 Nov;78(5):1410–1414. doi: 10.1172/JCI112729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Weisgraber K. H., Innerarity T. L., Mahley R. W. Role of lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts. J Biol Chem. 1978 Dec 25;253(24):9053–9062. [PubMed] [Google Scholar]
  49. Willnow T. E., Goldstein J. L., Orth K., Brown M. S., Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed] [Google Scholar]
  50. Willnow T. E., Sheng Z., Ishibashi S., Herz J. Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science. 1994 Jun 3;264(5164):1471–1474. doi: 10.1126/science.7515194. [DOI] [PubMed] [Google Scholar]
  51. Woollett L. A., Spady D. K., Dietschy J. M. Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster. J Clin Invest. 1992 Apr;89(4):1133–1141. doi: 10.1172/JCI115694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Woollett L. A., Spady D. K., Dietschy J. M. Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate. J Lipid Res. 1992 Jan;33(1):77–88. [PubMed] [Google Scholar]
  53. Yamada N., Shames D. M., Stoudemire J. B., Havel R. J. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E. Proc Natl Acad Sci U S A. 1986 May;83(10):3479–3483. doi: 10.1073/pnas.83.10.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]

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