Skip to main content
SpringerLink
Log in

Diet-induced hypercholesterolemia alters liver glycosaminoglycans and associated-lipoprotein receptors in rats

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Glycosaminoglycans (GAGs) play an important role in lipoprotein metabolism. In liver, it facilitates the uptake of remnants through receptor-independent endocytosis. However, changes in liver GAGs during diet-induced hypercholesterolemia with normal levels of fat feeding are unknown. Present paper highlights the effect of diet-induced hypercholesterolemia with normal levels (5%) of fat on liver GAGs and other associated lipoprotein receptors. Hypercholesterolemia was induced in rats by feeding diet supplemented with 0.5% cholesterol and 0.125% bile salts. Hypercholesterolemia showed significantly decreased GAGs of both heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) classes of molecules. Quantitative real-time polymerase chain reaction analysis of GAG biosynthetic enzymes and other genes revealed significant changes in expression profile. The decrease in GAGs was prevented by simvastatin treatment; a drug that inhibits endogenous cholesterol synthesis that was used as a positive control in our study. Furthermore, there was a comparatively decreased binding of GAGs from hypercholesterolemic rats to lipoprotein lipase. LRP1 which plays a major role in lipoprotein uptake was also significantly decreased, and it was attenuated in simvastatin-treated hypercholesterolemic rats. Furthermore, LDLR and ApoE were also decreased significantly in liver of hypercholesterolemic rats. Thus, diet-induced hypercholesterolemia results in dysregulation of cholesterol homeostasis apparently through changes in GAGs in conjunction with other associated players.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

2AB:

2-Aminobenzamide

AIN-93G:

American Institute of Nutrition-93 Growth

ApoB:

Apolipoprotein B

ApoE:

Apolipoprotein E

AUC:

Area under curve

C4st1 :

Chondroitin 4 sulfotransferase 1

CAM:

Cellulose acetate membrane

CS/DS:

Chondroitin sulfate/dermatan sulfate

DMMB:

1,9-Dimethyl methylene blue

ECL:

Enhanced chemiluminescence

Ext1 :

Exostosin 1

GAGs:

Glycosaminoglycans

HDL-c:

High-density lipoprotein cholesterol

HL:

Hepatic lipase

HRP:

Horseradish peroxidase

HS:

Heparan sulfate

HSPG:

Heparan sulfate proteoglycan

CSPG:

Chondroitin sulfate proteoglycan

LDL-c:

Low-density lipoprotein cholesterol

LDLR:

Low-density lipoprotein receptor

Lpl:

Lipoprotein lipase

LRP1:

Low-density lipoprotein related protein 1

Ndst1 :

N-deacetylase/N-sulfotransferase 1

OFTT:

Oral fat tolerance test

PGs:

Proteoglycans

PVDF:

Polyvinylidene fluoride

qRT-PCR:

Quantitative real-time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

TBST:

Tris-buffered saline Tween-20

TG:

Triglyceride

TRLs:

Triglyceride-rich proteins

Ust :

Uronyl-2-sulfotransferase

VLDL:

Very low density lipoprotein

Xylt1 :

Xylosyltransferase 1

References

  1. Armitage J (2007) The safety of statins in clinical practice. Lancet 370:1781–1790

    Article  CAS  PubMed  Google Scholar 

  2. Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ (2010) Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER database. J Lipid Res 51:1546–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chandrashekhar S, Esterman MA, Hoffman MA (1987) Microdetermination of proteoglycans and glycosaminoglycans in the presence of guanidine hydrochloride. Anal Biochem 161:103–108

    Article  Google Scholar 

  4. Couchman JR, Pataki CA (2012) An introduction to proteoglycans and their localization. J Histochem Cytochem 60:885–897

    Article  PubMed  PubMed Central  Google Scholar 

  5. Deng Y, Foley EM, Gonzales JC, Gordts PL, Li Y, Esko JD (2012) Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance. Hepatology 55:277–286

    Article  CAS  PubMed  Google Scholar 

  6. Edwards IJ, Xu H, Obunike JC, Goldberg IJ, Wagner WD (1995) Differentiated macrophages synthesize a heparan sulfaye proteoglycan and an oversulfated chondroitin sulfate proteoglycan that bind lipoprotein lipase. Arterioscler Thromb Vasc Biol 15:400–409

    Article  CAS  PubMed  Google Scholar 

  7. Espirito Santo SM, Pires NM, Boesten LS, Gerritsen G, Bovenschen N, van Dijk KW, Jukema JW, Princen HM, Bensadoun A, Li WP, Herz J, Havekes LM, van Vlijmen BJ (2004) Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood 103:3777–3782

    Article  PubMed  Google Scholar 

  8. Fletcher MJ (1968) A colorimetric method for estimating serum triglycerides. Clin Chim Acta 22:393–397

    Article  CAS  PubMed  Google Scholar 

  9. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipid from animal tissue. J Biol Chem 226:497–506

    CAS  PubMed  Google Scholar 

  10. Foley EM, Gordts PL, Stanford KI, Gonzales JC, Lawrence R, Stoddard N, Esko JD (2013) Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol 33:2065–2074

    Article  CAS  PubMed  Google Scholar 

  11. Fungwe TV, Cagen L, Wilcox HG, Heimberg M (1992) Regulation of hepatic secretion of very low density lipoprotein by dietary cholesterol. J Lipid Res 33:179–191

    CAS  PubMed  Google Scholar 

  12. Gigli M, Ghisellia G, Torrib G, Naggib A, Rizzoa V (1993) A comparative study of low-density lipoprotein interaction with glycosaminoglycans. Biochim Biophys Acta Lipids Lipid Metab 1167:211–217

    Article  CAS  Google Scholar 

  13. Kiran G, Srikanth CB, Salimath PV, Nandini CD (2015) Diet-induced hypercholesterolemia imparts structure-function changes to erythrocyte chondroitin sulfate/dermatan sulfate. J Biochem 158:217–224

    Article  CAS  PubMed  Google Scholar 

  14. Kjellen L, Bielefeld D, Hook M (1983) Reduced sulfation of liver heparan sulfate in experimentally diabetic rats. Diabetes 32:337–342

    Article  CAS  PubMed  Google Scholar 

  15. Linton MF, Hasty AH, Babaev VR, Fazio S (1998) Hepatic Apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor. J Clin Invest 101:1726–1736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  17. MacArthur JM, Bishop JR, Stanford KI, Wang L, Bensadoun A, Witztum JL, Esko JD (2007) Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J Clin Invest 117:153–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mahley RW (1981) Cellular and molecular biology of lipoprotein metabolism in atherosclerosis. Diabetes 30:60–65

    Article  CAS  PubMed  Google Scholar 

  19. Mahley RW, Ji ZS (1999) Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 40:1–16

    CAS  PubMed  Google Scholar 

  20. Martı’nez-Beamonte R, Navarro MA, Acin S, Guille’n N, Barranquero C, Arnal C, Surra J, Osada J (2013) Postprandial changes in high density lipoproteins in rats subjected to gavage administration of virgin olive oil. PLoS One 8:e55231

    Article  Google Scholar 

  21. Martins IJ, Hone E, Chi C, Seydel U, Martins RN, Redgrave TG (2000) Relative roles of LDLr and LRP in the metabolism of chylomicron remnants in genetically manipulated mice. J Lipid Res 41:205–213

    CAS  PubMed  Google Scholar 

  22. Mooij HL, Bernelot Moens SJ, Gordts PLSM, Stanford KI, Foley EM, van den Boogert MAW, Witjes JJ, Carlijne Hassing H, Tanck MW, van de Sande MAJ, Levels JH, Kastelein JJ, Stroes ES, Dallinga-Thie GM, Esko JD, Nieuwdorp M (2015) Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. J Lipid Res 56:665–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Planer D, Metzger S, Zcharia E, Wexler ID, Vlodavsky I, Chajek-Shaul T (2011) Role of heparanase on hepatic uptake of intestinal derived lipoprotein and fatty streak formation in mice. PLoS One 6:e18370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Qu S, Perdomo G, Su D, D’Souza FM, Shachter NS, Dong HH (2007) Effects of apoA-V on HDL and VLDL metabolism in APOC3 transgenic mice. J Lipid Res 48:1476–1487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rasband WS (1997-2016) ImageJ, U. S. National Institutes of Health, Bethesda http://imagej.nih.gov/ij/

  26. Reeves PG, Nielsen FH, Fahey GC Jr (1993a) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951

    CAS  PubMed  Google Scholar 

  27. Scott JE (1960) Aliphatic ammonium salts in the assay of acidic polysaccharides from tissues. Methods Biochem Anal 8:145–197

    CAS  PubMed  Google Scholar 

  28. Srikanth CB, Salimath PV, Nandini CD (2012) Erythrocytes express chondroitin sulfate/dermatan sulfate, which undergoes quantitative changes during diabetes and mediate erythrocyte adhesion to extracellular matrix components. Biochimie 94:1347–1355

    Article  CAS  PubMed  Google Scholar 

  29. Staprans I, Felts JM (1985) Isolation and characterization of glycosaminoglycans in human plasma. J Clin Invest 76:1984–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sultan F, Cardona-Sanclemente LE, Lagrange D, Lutton C, Griglio S (1990) Lipoprotein lipase and hepatic lipase activities in a hypercholesterolemic (RICO) strain of rat. Effect of dietary cholesterol. Biochem J 266:349–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tasdelen I, Berger R, Kalkhoven E (2013) PPARγ regulates expression of carbohydrate sulfotransferase 11 (CHST11/C4ST1), a regulator of LPL cell surface binding. PLoS One 8:e64284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang YM, Zhang B, Xue Y, Li ZJ, Wang JF, Xue CH, Yanagita T (2010) The mechanism of dietary cholesterol effects on lipids metabolism in rats. Lipids Health Dis 9:4

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yamaguchi Y, Inatani M, Matsumoto Y, Ogawa J, Irie F (2010) Role of heparan sulfate in mammalian brain development current views based on the findings from Ext1 conditional knockout studies. Prog Mol Bol Transl Sci 93:133–152

    Article  CAS  Google Scholar 

  34. Young EK, Chatterjee C, Sparks DL (2009) HDL-ApoE content regulates the displacement of hepatic lipase from cell surface proteoglycs. Am J Pathol 175:448–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zeng BJ, Mortimer BC, Martins IJ, Seydel U, Redgrave TG (1998) Chylomicron remnant uptake is regulated by the expression and function of heparan sulfate proteoglycan in hepatocytes. J Lipid Res 39:845–860

    CAS  PubMed  Google Scholar 

  36. Zlatkis A, Zak B (1969) Study of a new cholesterol reagent. Anal Biochem 29:143–148

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Kiran G acknowledges ICMR (3/1/2/25/11RHN), New Delhi, for the award of research fellowship. CSIR is acknowledged for the financial support, and Director of CSIR-CFTRI is acknowledged for his kind support and interest in this work.

Author information

Authors and Affiliations

  1. Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysuru, Karnataka, 570 020, India

    Gangappa Kiran, Ummiti J. S. Prasada Rao & Paramahans V. Salimath

  2. JSS Medical College, Mysuru, Karnataka, 570 015, India

    Paramahans V. Salimath

  3. Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, Karnataka, 570 020, India

    Nandini D. Chilkunda

Authors
  1. Gangappa Kiran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ummiti J. S. Prasada Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paramahans V. Salimath
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nandini D. Chilkunda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nandini D. Chilkunda.

Ethics declarations

Conflict of interests

The authors declare that there is no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kiran, G., Prasada Rao, U.J.S., Salimath, P.V. et al. Diet-induced hypercholesterolemia alters liver glycosaminoglycans and associated-lipoprotein receptors in rats. J Physiol Biochem 73, 539–550 (2017). https://doi.org/10.1007/s13105-017-0583-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-017-0583-z

Keywords

Search

Navigation