Skip to main content
SpringerLink
Log in

The Role of Cell Surface Receptors in Lp(a) Catabolism

  • Chapter
  • First Online:
Lipoprotein(a)

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 499 Accesses

Abstract

Lipoprotein(a) [Lp(a)] is a unique variant of low-density lipoprotein (LDL) which imparts a significant risk of developing cardiovascular disease. Lp(a) is defined by the large apolipoprotein(a) [apo(a)] glycoprotein which is polymorphic in size and is synthesised in the liver before addition to LDL. The main clearance route for Lp(a) is via the liver with some role for the kidneys. Unlike LDL, there is no clear pathway of catabolism for Lp(a). Both liver and kidney express a range of different receptors which bind to various ligands on the Lp(a) molecule to promote Lp(a) uptake. In this chapter, we give an overview of the various cell surface receptors reported to be involved in Lp(a) catabolism.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271(5248):518–20.

    CAS  PubMed  Google Scholar 

  • Albers JJ, Koschinsky ML, Marcovina SM. Evidence mounts for a role of the kidney in lipoprotein(a) catabolism. Kidney Int. 2007;71(10):961–2.

    CAS  PubMed  Google Scholar 

  • Argraves KM, Kozarsky KF, Fallon JT, Harpel PC, Strickland DK. The atherogenic lipoprotein [Lp(a)] is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest. 1997;100(9):2170–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Becker L, Cook PM, Wright TG, Koschinsky ML. Quantitative evaluation of the contribution of weak lysine-binding sites present within apolipoprotein(a) kringle IV types 6-8 to lipoprotein(a) assembly. J Biol Chem. 2004;279(4):2679–88.

    CAS  PubMed  Google Scholar 

  • Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature. 1989;341(6238):162–4.

    CAS  PubMed  Google Scholar 

  • Berg K. A new serum type system in man—the Lp system. Acta Pathol Microbiol Scand. 1963;59(3):369–82.

    CAS  PubMed  Google Scholar 

  • Bharadwaj A, Kempster E, Waisman DM. The Annexin A2/S100A10 complex: the mutualistic symbiosis of two distinct proteins. Biomol. 2021;11(12):1849.

    Google Scholar 

  • Black IW, Wilcken DE. Decreases in apolipoprotein(a) after renal transplantation: implications for lipoprotein(a) metabolism. Clin Chem. 1992;38(3):353–7.

    CAS  PubMed  Google Scholar 

  • Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34–47.

    CAS  PubMed  Google Scholar 

  • Brunner C, Lobentanz EM, Petho-Schramm A, Ernst A, Kang C, Dieplinger H, et al. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells. J Biol Chem. 1996;271(50):32403–10.

    CAS  PubMed  Google Scholar 

  • Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D, et al. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res. 2005;46(12):2681–91.

    CAS  PubMed  Google Scholar 

  • Chellan B, Narayani J, Appukuttan PS. Galectin-1, an endogenous lectin produced by arterial cells, binds lipoprotein(a) [Lp(a)] in situ: relevance to atherogenesis. Exp Mol Pathol. 2007;83(3):399–404.

    CAS  PubMed  Google Scholar 

  • Chemello K, Beeské S, Trang Tran TT, Blanchard V, Villard EF, Poirier B, et al. Lipoprotein(a) cellular uptake ex vivo and hepatic capture in vivo is insensitive to PCSK9 inhibition with alirocumab. JACC Basic Transl Sci. 2020;5(6):549–57.

    PubMed  PubMed Central  Google Scholar 

  • Chiesa G, Hobbs HH, Koschinsky ML, Lawn RM, Maika SD, Hammer RE. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a). J Biol Chem. 1992;267(34):24369–74.

    CAS  PubMed  Google Scholar 

  • Christensen EI, Birn H. Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol. 2001;280(4):F562–73.

    CAS  PubMed  Google Scholar 

  • Coassin S, Erhart G, Weissensteiner H, Guimarães E, de Araújo M, Lamina C, Schönherr S, et al. A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. Eur Heart J. 2017;38(23):1823–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Floren CH, Albers JJ, Bierman EL. Uptake of Lp(a) lipoprotein by cultured fibroblasts. Biochem Biophys Res Commun. 1981;102(2):636–9.

    CAS  PubMed  Google Scholar 

  • Gabel BR, Koschinsky ML. Sequences within apolipoprotein(a) kringle IV types 6-8 bind directly to low-density lipoprotein and mediate noncovalent association of apolipoprotein(a) with apolipoprotein B-100. Biochemistry. 1998;37(21):7892–8.

    CAS  PubMed  Google Scholar 

  • Hajjar KA, Krishnan S. Annexin II: a mediator of the plasmin/plasminogen activator system. Trends Cardiovasc Med. 1999;9(5):128–38.

    CAS  PubMed  Google Scholar 

  • Havekes L, Vermeer BJ, Brugman T, Emeis J. Binding of Lp(a) to the low density lipoprotein receptor of human fibroblasts. FEBS Lett. 1981;132(2):169–73.

    CAS  PubMed  Google Scholar 

  • Hoover-Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism. 2013;62(4):479–91.

    CAS  PubMed  Google Scholar 

  • Hrzenjak A, Frank S, Wo X, Zhou Y, Van Berkel T, Kostner GM. Galactose-specific asialoglycoprotein receptor is involved in lipoprotein(a) catabolism. Biochem J. 2003;376(3):765–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Igdoura SA. Asialoglycoprotein receptors as important mediators of plasma lipids and atherosclerosis. Curr Opin Lipidol. 2017;28(2):209–12.

    CAS  PubMed  Google Scholar 

  • Knight BL. Lp(a) catabolism in hypercholesterolaemic individuals. Chem Phys Lipids. 1994;67-68:233–9.

    CAS  PubMed  Google Scholar 

  • Koschinsky ML, Cote GP, Gabel B, van der Hoek YY. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100. J Biol Chem. 1993;268(26):19819–25.

    CAS  PubMed  Google Scholar 

  • Kostner KM, Maurer G, Huber K, Stefenelli T, Dieplinger H, Steyrer E, et al. Urinary excretion of apo(a) fragments. Role in apo(a) catabolism. Arterioscler Thromb Vasc Biol. 1996;16(8):905–11.

    CAS  PubMed  Google Scholar 

  • Kostner KM, Marz W, Kostner GM. When should we measure lipoprotein (a)? Eur Heart J. 2013;34(42):3268–76.

    CAS  PubMed  Google Scholar 

  • Kraft HG, Lingenhel A, Pang RW, Delport R, Trommsdorff M, Vermaak H, et al. Frequency distributions of apolipoprotein(a) kringle IV repeat alleles and their effects on lipoprotein(a) levels in Caucasian, Asian, and African populations: the distribution of null alleles is non-random. Eur J Hum Genet. 1996;4(2):74–87.

    CAS  PubMed  Google Scholar 

  • Krempler F, Kostner GM, Roscher A, Haslauer F, Bolzano K, Sandhofer F. Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man. J Clin Invest. 1983;71(5):1431–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kruth HS, Jones NL, Huang W, Zhao B, Ishii I, Chang J, et al. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J Biol Chem. 2005;280(3):2352–60.

    CAS  PubMed  Google Scholar 

  • Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res. 2013;54(10):2815–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marz W, Beckmann A, Scharnagl H, Siekmeier R, Mondorf U, Held I, et al. Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. FEBS Lett. 1993;325(3):271–5.

    CAS  PubMed  Google Scholar 

  • McCormick SPA, Schneider WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–64.

    CAS  PubMed  Google Scholar 

  • McCormick SP, Ng JK, Taylor S, Flynn LM, Hammer RE, Young SG. Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a). Proc Natl Acad Sci U S A. 1995;92(22):10147–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  • McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987;330(6144):132–7.

    CAS  PubMed  Google Scholar 

  • Morgan BM, Brown AN, Deo N, Harrop TWR, Taiaroa G, Mace PD, et al. Nonsynonymous SNPs in LPA homologous to plasminogen deficiency mutants represent novel null apo(a) alleles. J Lipid Res. 2020;61(3):432–44.

    CAS  PubMed  Google Scholar 

  • Niemeier A, Willnow T, Dieplinger H, Jacobsen C, Meyer N, Hilpert J, et al. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro. Arterioscler Thromb Vasc Biol. 1999;19(3):552–61.

    CAS  PubMed  Google Scholar 

  • Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest. 1995;95(3):1403–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reblin T, Niemeier A, Meyer N, Willnow TE, Kronenberg F, Dieplinger H, et al. Cellular uptake of lipoprotein[a] by mouse embryonic fibroblasts via the LDL receptor and the LDL receptor-related protein. J Lipid Res. 1997;38(10):2103–10.

    CAS  PubMed  Google Scholar 

  • Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42(1):e48–60.

    CAS  PubMed  Google Scholar 

  • Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem. 2015;290(18):11649–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Romagnuolo R, Scipione CA, Marcovina SM, Gemin M, Seidah NG, Boffa MB, et al. Roles of the low density lipoprotein receptor and related receptors in inhibition of lipoprotein(a) internalization by proprotein convertase subtilisin/kexin type 9. PLoS One. 2017;12(7):e0180869.

    PubMed  PubMed Central  Google Scholar 

  • Schachtl-Riess JF, Kheirkhah A, Grüneis R, Maio SD, Schoenherr S, Streiter G, et al. Frequent LPA KIV-2 variants lower lipoprotein(a) concentrations and protect against coronary artery disease. J Am Coll Cardiol. 2021;78(5):437–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scipione CA, Sayegh SE, Romagnuolo R, Tsimikas S, Marcovina SM, Boffa MB, et al. Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a). J Lipid Res. 2015;56(12):2273–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12(5):467–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma M, Von Zychlinski-Kleffmann A, Porteous CM, Jones GT, Williams MJ, McCormick SP. Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids. J Lipid Res. 2015;56(7):1318–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma M, Redpath GM, Williams MJ, McCormick SP. Recycling of apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a). Circ Res. 2017;120(7):1091–102.

    CAS  PubMed  Google Scholar 

  • Siddiqui H, Yevstigneyev N, Madani G, McCormick S. Approaches to visualising endocytosis of LDL-related lipoproteins. Biomol. 2022;12(2):158.

    Google Scholar 

  • Tam SP, Zhang X, Koschinsky ML. Interaction of a recombinant form of apolipoprotein[a] with human fibroblasts and with the human hepatoma cell line HepG2. J Lipid Res. 1996;37(3):518–33.

    CAS  PubMed  Google Scholar 

  • Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901–44.

    CAS  PubMed  Google Scholar 

  • Tomlinson JE, McLean JW, Lawn RM. Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis. J Biol Chem. 1989;264(10):5957–65.

    CAS  PubMed  Google Scholar 

  • Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60(8):716–21.

    CAS  PubMed  Google Scholar 

  • Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC focus seminar 2/4. J Am Coll Cardiol. 2021;77(12):1576–89.

    CAS  PubMed  Google Scholar 

  • Van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation. 2016;134(8):611–24.

    PubMed  PubMed Central  Google Scholar 

  • Von Zychlinski A, Kleffmann T, Williams MJ, McCormick SP. Proteomics of lipoprotein(a) identifies a protein complement associated with response to wounding. J Proteome. 2011;74(12):2881–91.

    Google Scholar 

  • Wang N, Arai T, Ji Y, Rinninger F, Tall AR. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein apoB, low density lipoprotein apoB, and high density lipoprotein in transgenic mice. J Biol Chem. 1998;273(49):32920–6.

    CAS  PubMed  Google Scholar 

  • White AL, Lanford RE. Cell surface assembly of lipoprotein(a) in primary cultures of baboon hepatocytes. J Biol Chem. 1994;269(46):28716–23.

    CAS  PubMed  Google Scholar 

  • White AL, Guerra B, Lanford RE. Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum. J Biol Chem. 1997;272(8):5048–55.

    CAS  PubMed  Google Scholar 

  • Yang XP, Amar MJ, Vaisman B, Bocharov AV, Vishnyakova TG, Freeman LA, et al. Scavenger receptor-BI is a receptor for lipoprotein(a). J Lipid Res. 2013;54(9):2450–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Sethi A, Yanek LR, Knapper C, Nordestgaard BG, Tybjaerg-Hansen A, et al. SCARB1 gene variants are associated with the phenotype of combined high high-density lipoprotein cholesterol and high lipoprotein(a). Circ Cardiovasc Genet. 2016;9(5):408–18.

    CAS  PubMed  Google Scholar 

  • Yeang C, Hung MY, Byun YS, Clopton P, Yang X, Witztum JL, et al. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a). J Clin Lipidol. 2016;10(3):594–603.

    PubMed  Google Scholar 

  • Zanoni P, Velagapudi S, Yalcinkaya M, Rohrer L, von Eckardstein A. Endocytosis of lipoproteins. Atherosclerosis. 2018;275:273–95.

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Lamia Ismail and Déanna Shea contributed equally with all other contributors.

Authors and Affiliations

  1. Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand

    Lamia Ismail, Déanna Shea & Sally McCormick

Authors
  1. Lamia Ismail
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Déanna Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sally McCormick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sally McCormick .

Editor information

Editors and Affiliations

  1. Mater Hospital, University of Queensland, Brisbane, QLD, Australia

    Karam Kostner

  2. Medical University of Graz, Graz, Austria

    Gerhard M. Kostner

  3. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

Ethics declarations

Nothing to disclose for all authors.

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ismail, L., Shea, D., McCormick, S. (2023). The Role of Cell Surface Receptors in Lp(a) Catabolism. In: Kostner, K., Kostner, G.M., Toth, P.P. (eds) Lipoprotein(a). Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-24575-6_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-24575-6_7

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-24574-9

  • Online ISBN: 978-3-031-24575-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation