Lipoprotein(a)

From Wikipedia, the free encyclopedia


Lipoprotein, Lp(a)
PDB rendering based on 1i71.
Available structures: 1i71, 1jfn, 1kiv, 2feb, 3kiv, 4kiv
Identifiers
Symbol(s) LPA; AK38; APOA; LP
External IDs OMIM: 152200 HomoloGene: 87856
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 4018 n/a
Ensembl ENSG00000198670 n/a
Uniprot P08519 n/a
Refseq XM_941792 (mRNA)
XP_946885 (protein)		 n/a (mRNA)
n/a (protein)
Location Chr 6: 160.87 - 161.01 Mb n/a
Pubmed search [1] n/a

Lipoprotein(a) (also called Lp(a)) is a lipoprotein subclass. Studies have identified Lp(a) as a putative risk factor for atherosclerotic diseases as coronary heart disease and stroke.[1][2][3]

Contents

[edit] Structure

Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a) [apo(a)], which is covalently bound to the apoB of the LDL like particle. Lp(a) plasma concentrations are highly heritable and mainly controlled by the apolipoprotein(a) gene [LPA] located on chromosome 6q26-27. Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of so called kringle IV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to > 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids).[4][5] These variable apo(a) sizes are known as "apo(a) isoforms". There is a general inverse correlation between the size of the apo(a)isoform and the Lp(a) plasma concentration[6] which is caused by a variable rate of degradation before the apo(a) protein has matured for Lp(a) assembly.[7][8] Apo(a) is express by the liver cells (hepatocytes), and the assembly of apo(a) and LDL particles seems to take place at the outer hepatocyte surface. The half-life of Lp(a) in the circulation is about 3 to 4 days.[9]

[edit] Catabolism and clearance

The mechanism and sites of Lp(a) catabolism are largely unknown. Uptake via the LDL receptor is not a major pathway of Lp(a)metabolism.[10][11] The kidney has been identified as playing a role in Lp(a) clearance from plasma.[12]

[edit] Populations

Lp(a) concentrations vary over one thousandfold between individuals, from < 0.2 to > 200 mg/dL. This range of concentrations is observed in all populations studied so far. The mean and median concentrations between different world populations show distinct particularities, the main being the two- to threefold higher Lp(a) plasma concentration of populations of African descent compared to Asian, Oceanic, or European populations. The general inverse correlation between apo(a) isoform size and Lp(a)plasma concentration is observed in all populations, however, mean Lp(a) associated with certain apo(a) isoforms varies between populations.

[edit] Function

The physiological function of Lp(a)/apo(a) is still unknown. A function within the coagulation system seems plausible, given the aspect of the high homology between apo(a) and plasminogen.[4] In fact, the LPA gene derives from a duplication of the plasminogen gene.

Other functions have been related to recruitment of inflammatory cells through interaction with Mac-1 integrin, angiogenesis, and wound healing.

However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. Thus plasma Lp(a) is certainly not vital, at least under normal environmental conditions. Since apo(a)/Lp(a) derived rather recently in mammalian evolution - only old world monkeys and humans have been shown to harbour Lp(a) - its function might not be vital but just evolutionary advantageous under certain environmental condition, e.g. in case of exposure to certain infectious disease.

[edit] Pathology

Lipoprotein's structure is similar to plasminogen and tPA (tissue plasminogen activator) and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Also because Lp(a) stimulates secretion of PAI-1 it leads to thrombogenesis. In addition, because of LDL cholesterol content, Lp-a contributes to atherosclerosis.[3][13]

[edit] Lipoprotein(a) and Disease

High Lp(a) in blood is a risk factor for coronary heart disease (CHD), cerebrovascular disease (CVD), atherosclerosis, thrombosis, and stroke.[14] Lp-a concentrations may be affected by disease states, but are only slightly affected by diet, exercise, and other environmental factors. Commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Niacin (nicotinic acid) and aspirin are two relatively safe, easily available and inexpensive drugs known to significantly reduce the levels of Lp(a) in some individuals with high Lp(a); they should be used under the supervision of a qualified physician.

High Lp(a) predicts risk of early atherosclerosis similar to high LDL, but in advanced atherosclerosis, Lp(a) is an independent risk factor not dependent on LDL. Lp(a) then indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains that are very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits binding of PLG to the cell surface, reducing plasmin generation which increases clotting. This inhibition of PLG by Lp(a) also promotes proliferation of smooth muscle cells. These unique features of Lp(a) suggest Lp(a) causes generation of clots and atherosclerosis.[15]

 This section does not cite any references or sources. (February 2008)
Please help improve this section by adding citations to reliable sources. Unverifiable material may be challenged and removed.

Vegetarians have higher levels of Lp-a than fish eaters in one homogeneous tribal population of Tanzania raising the possibility that pharmacologic amounts of fish oil supplements may be helpful to lower the levels of Lp-a.

Low fat-high carbohydrate diet raises Lp-a.

Fibrates such as benzafibrate or gemfibrozil have significantly lowered Lp-a in some individuals.

Prolonged and daily intake of large amounts of milk protein (casein) or alcohol extracted soy protein in the diet leads to a very significant decline in the levels of plasma Lp-a. However, consumption of regular soy protein does not lower the levels of Lp-a.

Regular consumption of moderate amounts of alcohol leads to significant decline in plasma levels of Lp-a.

High levels of Apo AI HDL cholesterol are protective against atherogenic potential of Lp-a.

[edit] Cardiology diagnostic tests

Lp(a) cannot yet be regarded as a conventional, well established risk factor for cardiovascular disease, although studies show an ASSOCIATION of Lp(a) and cardiovascular disease, which does not automatically mean a causal relation.[1] While it might well be indicated to measure Lp(a) in high risk patients, the association of Lp(a) and cardiovascular disease is rather complicated.[16] Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter.[17][18] Furthermore, the ethnic origin of an individual must be considered when evaluating its Lp(a) concentration in respect of the risk for cardiovascular events.[19][20] E.g. the "conventional" risk threshold of 30 mg/dl would classify up to > 50% of the individuals in some African populations as being at risk.[21][22][23] Furthermore, Lp(a) measurement is in urgent need of standardisation.[24]

Thus the threshold values given below should be seen very critically. They are -if at all- only applicable to individuals of European descent.

Lipoprotein(a) - Lp(a)[25]

Desirable: < 14 mg/dL
Borderline risk: 14 - 30 mg/dL
High risk: 31 - 50 mg/dL
Very high risk: > 50 mg/dL

[edit] See also

[edit] References

  1. ^ a b Danesh J, Collins R, Peto R (2000). "Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies". Circulation 102 (10): 1082–5. PMID 10973834. 
  2. ^ Smolders B, Lemmens R, Thijs V (2007). "Lipoprotein (a) and stroke: a meta-analysis of observational studies". Stroke 38 (6): 1959–66. doi:10.1161/STROKEAHA.106.480657. PMID 17478739. 
  3. ^ a b Schreiner PJ, Morrisett JD, Sharrett AR, Patsch W, Tyroler HA, Wu K, Heiss G (1993). "Lipoprotein(a) as a risk factor for preclinical atherosclerosis". Arterioscler. Thromb. 13 (6): 826–33. PMID 8499402. 
  4. ^ a b McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM (1987). "cDNA sequence of human apolipoprotein(a) is homologous to plasminogen". Nature 330 (6144): 132–7. doi:10.1038/330132a0. PMID 3670400. 
  5. ^ Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C (1987). "Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma". J. Clin. Invest. 80 (2): 458–65. PMID 2956279. 
  6. ^ Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Császár A, Boerwinkle E, Utermann G (1991). "Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups". Hum. Genet. 86 (6): 607–14. PMID 2026424. 
  7. ^ White AL, Rainwater DL, Hixson JE, Estlack LE, Lanford RE (1994). "Intracellular processing of apo(a) in primary baboon hepatocytes". Chem. Phys. Lipids 67-68: 123–33. PMID 8187206. 
  8. ^ Brunner C, Lobentanz EM, Pethö-Schramm A, Ernst A, Kang C, Dieplinger H, Müller HJ, Utermann G (1996). "The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells". J. Biol. Chem. 271 (50): 32403–10. doi:10.1074/jbc.271.50.32403. PMID 8943305. 
  9. ^ Rader DJ, Cain W, Zech LA, Usher D, Brewer HB (1993). "Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production". J. Clin. Invest. 91 (2): 443–7. PMID 8432853. 
  10. ^ Knight BL, Perombelon YF, Soutar AK, Wade DP, Seed M (1991). "Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects". Atherosclerosis 87 (2-3): 227–37. PMID 1830206. 
  11. ^ Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, Hoeg JM, Davignon J, Lupien P, Grossman M (1995). "The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans". J. Clin. Invest. 95 (3): 1403–8. PMID 7883987. 
  12. ^ Albers JJ, Koschinsky ML, Marcovina SM (2007). "Evidence mounts for a role of the kidney in lipoprotein(a) catabolism". Kidney Int. 71 (10): 961–2. doi:10.1038/sj.ki.5002240. PMID 17495935. 
  13. ^ Sotiriou SN, Orlova VV, Al-Fakhri N, Ihanus E, Economopoulou M, Isermann B, Bdeir K, Nawroth PP, Preissner KT, Gahmberg CG, Koschinsky ML, Chavakis T (2006). "Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin". FASEB J. 20 (3): 559–61. doi:10.1096/fj.05-4857fje. PMID 16403785. 
  14. ^ Christian Wilde (2003). Hidden Causes of Heart Attack and Stroke: Inflammation, Cardiology's New Frontier. Abigon Press, pages 182-183. ISBN 0-9724959-0-8. 
  15. ^ Caplice NM, Panetta C, Peterson TE, Kleppe LS, Mueske CS, Kostner GM, Broze GJ, Simari RD (2001). "Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis". Blood 98 (10): 2980–7. doi:10.1182/blood.V98.10.2980. PMID 11698280. 
  16. ^ Berglund L, Ramakrishnan R (2004). "Lipoprotein(a): an elusive cardiovascular risk factor". Arterioscler. Thromb. Vasc. Biol. 24 (12): 2219–26. doi:10.1161/01.ATV.0000144010.55563.63. PMID 15345512. 
  17. ^ Klausen IC, Sjøl A, Hansen PS, Gerdes LU, Møller L, Lemming L, Schroll M, Faergeman O (1997). "Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study". Atherosclerosis 132 (1): 77–84. doi:10.1016/S0021-9150(97)00071-3. PMID 9247362. 
  18. ^ Paultre F, Pearson TA, Weil HF, Tuck CH, Myerson M, Rubin J, Francis CK, Marx HF, Philbin EF, Reed RG, Berglund L (2000). "High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men". Arterioscler. Thromb. Vasc. Biol. 20 (12): 2619–24. PMID 11116062. 
  19. ^ Dahlén GH, Ekstedt B (2001). "The importance of the relation between lipoprotein(a) and lipids for development of atherosclerosis and cardiovascular disease". J. Intern. Med. 250 (3): 265–7. doi:10.1046/j.1365-2796.2001.00889.x. PMID 11555135. 
  20. ^ G. H. Dahlen and B. Ekstedt, J.Intern.Med 250, 265-267 (2001)
  21. ^ Helmhold M, Bigge J, Muche R, Mainoo J, Thiery J, Seidel D, Armstrong VW (1991). "Contribution of the apo[a phenotype to plasma Lp(a) concentrations shows considerable ethnic variation]". J. Lipid Res. 32 (12): 1919–28. PMID 1840066. 
  22. ^ Cobbaert C, Mulder P, Lindemans J, Kesteloot H (1997). "Serum LP(a) levels in African aboriginal Pygmies and Bantus, compared with Caucasian and Asian population samples". J Clin Epidemiol 50 (9): 1045–53. doi:10.1016/S0895-4356(97)00129-7. PMID 9363039. 
  23. ^ Schmidt K, Kraft HG, Parson W, Utermann G (2006). "Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon". Eur. J. Hum. Genet. 14 (2): 190–201. doi:10.1038/sj.ejhg.5201512. PMID 16267501. 
  24. ^ Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, Sakurabayashi I, Tate JR, Steinmetz A (2000). "Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a)". Clin. Chem. 46 (12): 1956–67. PMID 11106328. 
  25. ^ Ryan, George M; Julius Torelli (2005). Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you. New York: St. Martin's Griffin, page 91. ISBN 0-312-34863-0. 

[edit] Further reading

  • Utermann G (1989). "The mysteries of lipoprotein(a).". Science 246 (4932): 904–10. PMID 2530631. 
  • Salonen EM, Jauhiainen M, Zardi L, et al. (1990). "Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it.". EMBO J. 8 (13): 4035–40. PMID 2531657. 
  • Frank SL, Klisak I, Sparkes RS, et al. (1988). "The apolipoprotein(a) gene resides on human chromosome 6q26-27, in close proximity to the homologous gene for plasminogen.". Hum. Genet. 79 (4): 352–6. PMID 3410459. 
  • McLean JW, Tomlinson JE, Kuang WJ, et al. (1987). "cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.". Nature 330 (6144): 132–7. doi:10.1038/330132a0. PMID 3670400. 
  • Scanu AM, Pfaffinger D, Lee JC, Hinman J (1994). "A single point mutation (Trp72-->Arg) in human apo(a) kringle 4-37 associated with a lysine binding defect in Lp(a).". Biochim. Biophys. Acta 1227 (1-2): 41–5. PMID 7918682. 
  • Grainger DJ, Kemp PR, Liu AC, et al. (1994). "Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice.". Nature 370 (6489): 460–2. doi:10.1038/370460a0. PMID 8047165. 
  • Mikol V, LoGrasso PV, Boettcher BR (1996). "Crystal structures of apolipoprotein(a) kringle IV37 free and complexed with 6-aminohexanoic acid and with p-aminomethylbenzoic acid: existence of novel and expected binding modes.". J. Mol. Biol. 256 (4): 751–61. doi:10.1006/jmbi.1996.0122. PMID 8642595. 
  • Edelstein C, Italia JA, Klezovitch O, Scanu AM (1997). "Functional and metabolic differences between elastase-generated fragments of human lipoprotein[a] and apolipoprotein[a]". J. Lipid Res. 37 (8): 1786–801. PMID 8864963. 
  • Edelstein C, Italia JA, Scanu AM (1997). "Polymorphonuclear cells isolated from human peripheral blood cleave lipoprotein(a) and apolipoprotein(a) at multiple interkringle sites via the enzyme elastase. Generation of mini-Lp(a) particles and apo(a) fragments.". J. Biol. Chem. 272 (17): 11079–87. PMID 9111002. 
  • Köchl S, Fresser F, Lobentanz E, et al. (1997). "Novel interaction of apolipoprotein(a) with beta-2 glycoprotein I mediated by the kringle IV domain.". Blood 90 (4): 1482–9. PMID 9269765. 
  • Bonen DK, Nassir F, Hausman AM, Davidson NO (1998). "Inhibition of N-linked glycosylation results in retention of intracellular apo[a] in hepatoma cells, although nonglycosylated and immature forms of apolipoprotein[a] are competent to associate with apolipoprotein B-100 in vitro.". J. Lipid Res. 39 (8): 1629–40. PMID 9717723. 
  • Niemeier A, Willnow T, Dieplinger H, et al. (1999). "Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro.". Arterioscler. Thromb. Vasc. Biol. 19 (3): 552–61. PMID 10073957. 
  • Edelstein C, Shapiro SD, Klezovitch O, Scanu AM (1999). "Macrophage metalloelastase, MMP-12, cleaves human apolipoprotein(a) in the linker region between kringles IV-4 and IV-5. Potential relevance to lipoprotein(a) biology.". J. Biol. Chem. 274 (15): 10019–23. PMID 10187779. 
  • Ogorelkova M, Gruber A, Utermann G (1999). "Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians.". Hum. Mol. Genet. 8 (11): 2087–96. PMID 10484779. 
  • Røsby O, Berg K (2000). "LPA gene: interaction between the apolipoprotein(a) size ('kringle IV' repeat) polymorphism and a pentanucleotide repeat polymorphism influences Lp(a) lipoprotein level.". J. Intern. Med. 247 (1): 139–52. PMID 10672142. 
  • Klose R, Fresser F, Kochl S, et al. (2001). "Mapping of a minimal apolipoprotein(a) interaction motif conserved in fibrin(ogen) beta - and gamma -chains.". J. Biol. Chem. 275 (49): 38206–12. doi:10.1074/jbc.M003640200. PMID 10980194. 
  • Ogorelkova M, Kraft HG, Ehnholm C, Utermann G (2001). "Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.". Hum. Mol. Genet. 10 (8): 815–24. PMID 11285247. 
  • Garner B, Merry AH, Royle L, et al. (2001). "Structural elucidation of the N- and O-glycans of human apolipoprotein(a): role of o-glycans in conferring protease resistance.". J. Biol. Chem. 276 (25): 22200–8. doi:10.1074/jbc.M102150200. PMID 11294842. 
  • Xue S, Madison EL, Miles LA (2003). "The Kringle V-protease domain is a fibrinogen binding region within Apo(a).". Thromb. Haemost. 86 (5): 1229–37. PMID 11816712. 

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