Skip to main content
SpringerLink
Log in

Hepatic cholesterol metabolism in experimental nephrotic syndrome

  • Published:
Lipids

Abstract

Hypercholesterolemia is a consistent feature of the nephrotic syndrome. However, the mechanisms underlying this perturbation are unclear. In the present work, we have investigated different factors that influence hepatic cholesterol metabolism using the nephrotic rat as a model. The induction of nephrosis resulted in a severe and sustained hypercholesterolemia. However, no effect on the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, could be detected. Further, plasma lathosterol/cholesterol ratio, a measure of cholesterol synthesis, was not altered. Also, plasma levels of mevalonate, both a substrate for cholesterogenesis beyond the rate-limiting step and a marker for cholesterol synthesis, did not differ between control rats and those with established hypercholesterolemia. There was no detectable change in the expression of low density lipoprotein (LDL) receptor between the two experimental groups. We conclude that the early increase in cholesterol synthesis reported after the induction of nephrosis is not necessary for the maintenance of hypercholeserolemia. Established hypercholesterolemia of the nephrotic syndrome seems to represent a steady state in which neither enhanced hepatic cholesterol synthesis nor retarded LDL cholesterol clearance is of major importance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

GFR:

glomerular filtration rate

HMG-CoA:

3-hydroxy-3-methylglutaryl CoA

LDL:

low density lipoprotein

PAN:

puromycin aminonucleoside

References

  1. Baxter, J.H. (1962) Hyperlipoproteinemia in Nephrosis, Arch. Int. Med. 109, 742–757.

    CAS  Google Scholar 

  2. Baxter, J.H., Goodman, H.C., and Havel, R.J. (1960) Serum Lipid and Lipoprotein Alterations in Nephrosis. J. Clin. Invest. 39, 455–464.

    Article  PubMed  CAS  Google Scholar 

  3. Marsh, J.B., and Sparks, C.E. (1979) Lipoproteins in Experimental Nephrosis: Plasma Levels and Composition, Metabolism 28, 1040–1045.

    Article  PubMed  CAS  Google Scholar 

  4. Berlyne, G.M., and Mallick, N.P., (1969) Ischaemic Heart Disease as a Complication of Nephrotic Syndrome, Lancet 2, 399–400.

    Article  PubMed  CAS  Google Scholar 

  5. Mallick, N.P., and Short, C.D. (1981) The Nephrotic Syndrome and Ischaemic Heart Disease, Nephron 27, 54–57.

    Article  PubMed  CAS  Google Scholar 

  6. Bernard, D.B. (1988) Extrarenal Complications of the Nephrotic Syndrome, Kidney Int. 33, 1184–1202.

    PubMed  CAS  Google Scholar 

  7. Grundy, S.M. (1990) Management of Hyperlipidemia of Kidney Disease, Kidney Int. 37, 847–853.

    PubMed  CAS  Google Scholar 

  8. Marsh, J.B., and Drabkin, D.L. (1955) Metabolic Channeling in Experimental Nephrosis. II. Lipide Metabolism, J. Biol. Chem. 212, 633–639.

    PubMed  CAS  Google Scholar 

  9. Gherardi, E. and Calandra, S. (1980) Experimental Nephrotic Syndrome Induced in the Rat by Puromycin Aminonucleoside: Hepatic Synthesis of Neutral Lipids and Phospholipids from 3H-Water and 3H-Palmitate Lipids 15, 108–112.

    PubMed  CAS  Google Scholar 

  10. Shafrir, E., and Brenner, T. (1979) Lipoprotein Lipid and Protein Synthesis in Experimental Nephrosis and Plasmapheresis. I: Studies in Rat in vivo. Lipids 14 695–702.

    PubMed  CAS  Google Scholar 

  11. Golper, T.A., Feingold, K.R., Fulford, M.H., and Siperstein, M.-D. (1986) The Role of Circulating Mevalonate in Nephrotic Hypercholesterolemia in the Rat. J. Lipid Res. 27, 1044–1051.

    PubMed  CAS  Google Scholar 

  12. Golper, T.A., and Swartz, S.H. (1982) Impaired Renal Mevalonate Metabolism in Nephrotic Syndrome: A Stimulus for Increased Hepatic Cholesterogenesis Independent of GFR and Hypoalbuminemia, Metabolism 31, 471–476.

    Article  PubMed  CAS  Google Scholar 

  13. Thabet, M.A.E.H., Challa, A., Chan, J.C.M., Pandak, W.M., Heuman, D.M., and Vlahcevic, Z.R. (1993) Studies of Alteration of Hepatic Cholesterol Metabolism in Puromycin-Induced Nephrotic Syndrome in Rats, Kidney Int. 44, 789–794.

    PubMed  CAS  Google Scholar 

  14. Joven, J., Masana, L., Villabona, C., Vilella, E., Bargallo, T., Trias, M., Figueras, M., and Turner, P.R. (1989) Low Density Lipoprotein Metabolism in Rats with Puromycin Aminonucleoside Induced Nephrotic Syndrome, Metabolism 38, 491–495.

    Article  PubMed  CAS  Google Scholar 

  15. Kempen, H.J.M., Glatz, J.F.C., Gevers Leuven, J.A., van der Voort, H.A., and Katan, M.B. (1988) Serum Lathosterol Concentration Is an Indicator of Whole-Body Cholesterol Synthesis in Humans, J. Lipid Res. 29, 1149–1155.

    PubMed  CAS  Google Scholar 

  16. Parker, T.S., McNamara, D.J., Brown, C.D., Kolb, R., Ahrens, E.H., Jr., Alberts, A.W., Tobert, J., Chen, J., and De Schepper, P.J. (1984) Plasma Mevalonate as a Measure of Cholesterol Synthesis in Man. J. Clin. Invest. 74, 795–804.

    PubMed  CAS  Google Scholar 

  17. Goldstein, J.L., and Brown, M.S. (1977) The Low Density Lipoprotein Pathway and Its Relation to Atherosclerosis, Annu. Rev. Biochem. 46, 897–930.

    Article  PubMed  CAS  Google Scholar 

  18. Lund, E., Sisfontes, L., Reihnér, E., and Björkhem, I. (1989) Determination of Serum Levels of Unesterified Lathosterol by Isotope Dilution-Mass Spectrometry, Scand. J. Clin. Lab. Invest. 49, 165–171.

    PubMed  CAS  Google Scholar 

  19. Lindenthal, B., and von Bergmann, K. (1994) Determination of Urinary Mevalonic Acid Using Isotope Dilution Technique, Biolog. Mass. Spectrom. 23, 445–450.

    Article  CAS  Google Scholar 

  20. Brown, M.S., Goldstein, J.L., and Dietschy, J.M. (1979) Active and Inactive Forms of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase in the Liver of the Rat: Comparison with the Rate of Cholesterol Synthesis in Different Physiological States, J. Biol. Chem. 254, 5144–5149.

    PubMed  CAS  Google Scholar 

  21. Rudling, M., Norstedt, G., Olivecrona, H., Reihnér, E., Gustafsson, J.-A., and Angelin, B. (1992) Importance of Growth Hormone for the Induction of Hepatic Low Density Lipoprotein Receptors, Proc. Natl. Acad. Sci. USA 89, 6983–6987.

    Article  PubMed  CAS  Google Scholar 

  22. Walker, W.G., and Mitch, W.E. (1988) in The Principles and Practice of Medicine (Harvey, A.M., Johns, R.J., McKusick, V.A., Owens, A.H., and Ross, R.S., eds.), 22nd edn., pp. 723–724. Appelton & Lange, San Mateo.

    Google Scholar 

  23. Björkhem, I., Miettinen, T., Reihnér, E., Ewerth, S., Angelin, B., and Einarsson, K. (1987) Correlation Between Serum Levels of Some Cholesterol Precursors and the Activity of HMG-CoA Reductase in Human Liver, J. Lipid Res. 28, 1137–1143.

    PubMed  Google Scholar 

  24. Duane, W.C. (1995) Serum Lathosterol Levels in Human Subjects Reflect Changes in Whole Body Cholesterol Synthesis Induced by Lovastatin But Not Dietary Cholesterol, J. Lipid Res. 36, 343–348.

    PubMed  CAS  Google Scholar 

  25. Marsh, J.B. (1984) Lipoprotein Metabolism in Experimental Nephrosis. J. Lipid Res. 25, 1619–1623.

    PubMed  CAS  Google Scholar 

  26. Marsh, J.B., and Sparks, C.E. (1979) Hepatic Secretion of Lipoproteins in the Rat and the Effect of Experimental Nephrosis, J. Clin. Invest. 64, 1229–1237.

    PubMed  CAS  Google Scholar 

  27. Pandak, W.M., Heuman, D.M., Hylemon, P.B., and Vlahcevic, Z.R. (1990) Regulation of Bile Acid Synthesis. IV. Interrelationship Between Cholesterol and Bile Acid Biosynthesis Pathways, J. Lipid Res. 31, 79–90.

    PubMed  CAS  Google Scholar 

  28. Dullaart, R.P.F., Gansevoort, R.T., Sluiter, W.J., de Zeeuw, D., and de Jong, P.E. (1996) The Serum Lathosterol to Cholesterol Ratio, an Index of Cholesterol Synthesis, Is Not Elevated in Patients with Glomerular Proteinuria and Is Not Associated with Improvement of Hyperlipidemia in Response to Antiproteinuric Treatment, Metabolism 45, 723–730.

    Article  PubMed  CAS  Google Scholar 

  29. Vaziri, N.D., and Liang, K.H. (1995) Hepatic HMG-CoA Reductase Gene Expression During the Course of Puromycin-Induced Nephrosis, Kidney Int. 48, 1979–1985.

    PubMed  CAS  Google Scholar 

  30. Edgren, B., and Hellström, K. (1972) In vivo Studies of the Metabolism of Mevalonic Acid in Nephrotic Rats, Nutr. Metab. 14, 331–338.

    CAS  Google Scholar 

  31. Subang, M.C., Stewart-Phillips, J.L., Pappu, A.S., Subang, R., and Gagnon, R.F. (1995) Possible Role of Mevalonate in the Hypercholesterolemia Seen in Experimental Chronic Renal Failure, Nephron 69, 151–154.

    Article  PubMed  CAS  Google Scholar 

  32. Rudling, M. (1992) Hepatic mRNA Levels for the LDL Receptor and HMG-CoA Reductase Show Coordinate Regulation in vivo, J. Lipid Res. 33, 493–501.

    PubMed  CAS  Google Scholar 

  33. Vaziri, N.D., and Liang, K.H. (1996) Down-Regulation of Hepatic LDL Receptor Expression in Experimental Nephrosis, Kidney Int. 50, 887–893.

    PubMed  CAS  Google Scholar 

  34. Kaysen, G.A. (1991) Hyperlipidemia of the Nephrotic Syndrome, Kidney Int. 39 (Suppl. 31), S8-S15.

    Google Scholar 

  35. Hirano, T., Furukawa, S., Kurokawa, M., Ebara, T., Dixon, J.L., and Nagano, S. (1995) Intracellular Apoprotein B Degradation Is Suppressed by Decreased Albumin Concentration in Hep G2 cells, Kidney Int. 47, 421–431.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Karolinska Institutet at Huddinge University Hospital, Huddinge, Sweden

    Mats Rudling

  2. Department of Clinical Pharmacology, University of Bonn, Germany

    Bernhard Lindenthal

  3. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York

    Lars Berglund

  4. Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Huddinge University Hospital, S-141 86, Huddinge, Sweden

    Ayman Al-Shurbaji & Elisabet Humble

Authors
  1. Ayman Al-Shurbaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabet Humble
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mats Rudling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernhard Lindenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lars Berglund
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayman Al-Shurbaji.

About this article

Cite this article

Al-Shurbaji, A., Humble, E., Rudling, M. et al. Hepatic cholesterol metabolism in experimental nephrotic syndrome. Lipids 33, 165–169 (1998). https://doi.org/10.1007/s11745-998-0192-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-998-0192-z

Keywords

Search

Navigation