Lipoprotein(a)

Lipoprotein(a) (also called Lp(a)) is a lipoprotein subclass. Studies have identified Lp(a) as a putative risk factor for atherosclerotic diseases such as coronary heart disease and stroke.cite journal | author = Danesh J, Collins R, Peto R | title = Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies | journal = Circulation | volume = 102 | issue = 10 | pages = 1082–5 | year = 2000 | pmid = 10973834 | doi = | issn = | url = http://circ.ahajournals.org/cgi/content/abstract/102/10/1082 ] cite journal | author = Smolders B, Lemmens R, Thijs V | title = Lipoprotein (a) and stroke: a meta-analysis of observational studies | journal = Stroke | volume = 38 | issue = 6 | pages = 1959–66 | year = 2007 | pmid = 17478739 | doi = 10.1161/STROKEAHA.106.480657 | issn = ] cite journal | author = Schreiner PJ, Morrisett JD, Sharrett AR, Patsch W, Tyroler HA, Wu K, Heiss G | title = Lipoprotein(a) as a risk factor for preclinical atherosclerosis | journal = Arterioscler. Thromb. | volume = 13 | issue = 6 | pages = 826–33 | year = 1993 | pmid = 8499402 | doi = | issn = | url = http://atvb.ahajournals.org/cgi/reprint/13/6/826.pdf ]

tructure

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).cite journal | author = McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM | title = cDNA sequence of human apolipoprotein(a) is homologous to plasminogen | journal = Nature | volume = 330 | issue = 6144 | pages = 132–7 | year = 1987 | pmid = 3670400 | doi = 10.1038/330132a0 | issn = ] cite journal | author = Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C | title = Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma | journal = J. Clin. Invest. | volume = 80 | issue = 2 | pages = 458–65 | year = 1987 | pmid = 2956279 | doi = | issn = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=2956279 ] 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 concentrationcite journal | author = Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Császár A, Boerwinkle E, Utermann G | title = Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups | journal = Hum. Genet. | volume = 86 | issue = 6 | pages = 607–14 | year = 1991 | pmid = 2026424 | doi = | issn = ] which is caused by a variable rate of degradation before the apo(a) protein has matured for Lp(a) assembly.cite journal | author = White AL, Rainwater DL, Hixson JE, Estlack LE, Lanford RE | title = Intracellular processing of apo(a) in primary baboon hepatocytes | journal = Chem. Phys. Lipids | volume = 67-68 | issue = | pages = 123–33 | year = 1994 | pmid = 8187206 | doi = | issn = ] cite journal | author = Brunner C, Lobentanz EM, Pethö-Schramm A, Ernst A, Kang C, Dieplinger H, Müller HJ, Utermann G | title = The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells | journal = J. Biol. Chem. | volume = 271 | issue = 50 | pages = 32403–10 | year = 1996 | pmid = 8943305 | doi = 10.1074/jbc.271.50.32403 | issn = ] 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.cite journal | author = Rader DJ, Cain W, Zech LA, Usher D, Brewer HB | title = Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production | journal = J. Clin. Invest. | volume = 91 | issue = 2 | pages = 443–7 | year = 1993 | pmid = 8432853 | doi = | issn = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8432853 ]

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.cite journal | author = Knight BL, Perombelon YF, Soutar AK, Wade DP, Seed M | title = Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects | journal = Atherosclerosis | volume = 87 | issue = 2-3 | pages = 227–37 | year = 1991 | pmid = 1830206 | doi = | issn = ] cite journal | author = Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, Hoeg JM, Davignon J, Lupien P, Grossman M | title = The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans | journal = J. Clin. Invest. | volume = 95 | issue = 3 | pages = 1403–8 | year = 1995 | pmid = 7883987 | doi = | issn = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7883987 ] The kidney has been identified as playing a role in Lp(a) clearance from plasma.cite journal | author = Albers JJ, Koschinsky ML, Marcovina SM | title = Evidence mounts for a role of the kidney in lipoprotein(a) catabolism | journal = Kidney Int. | volume = 71 | issue = 10 | pages = 961–2 | year = 2007 | pmid = 17495935 | doi = 10.1038/sj.ki.5002240 | issn = ]

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.

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.cite journal | author = McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM | title = cDNA sequence of human apolipoprotein(a) is homologous to plasminogen | journal = Nature | volume = 330 | issue = 6144 | pages = 132–7 | year = 1987 | pmid = 3670400 | doi = 10.1038/330132a0 | issn = ] 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.

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.cite journal | author = Schreiner PJ, Morrisett JD, Sharrett AR, Patsch W, Tyroler HA, Wu K, Heiss G | title = Lipoprotein(a) as a risk factor for preclinical atherosclerosis | journal = Arterioscler. Thromb. | volume = 13 | issue = 6 | pages = 826–33 | year = 1993 | pmid = 8499402 | doi = | issn = | url = http://atvb.ahajournals.org/cgi/reprint/13/6/826.pdf ] cite journal | author = 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 | title = Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin | journal = FASEB J. | volume = 20 | issue = 3 | pages = 559–61 | year = 2006 | pmid = 16403785 | doi = 10.1096/fj.05-4857fje | issn = ]

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.cite book | author = Christian Wilde | title = Hidden Causes of Heart Attack and Stroke: Inflammation, Cardiology's New Frontier | publisher = Abigon Press | location = | year = 2003 | pages = pages 182-183 | isbn = 0-9724959-0-8 | oclc = | doi = ] 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.cite journal | author = Caplice NM, Panetta C, Peterson TE, Kleppe LS, Mueske CS, Kostner GM, Broze GJ, Simari RD | title = Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis | journal = Blood | volume = 98 | issue = 10 | pages = 2980–7 | year = 2001 | pmid = 11698280 | doi = 10.1182/blood.V98.10.2980 | issn = ]

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.

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

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.

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.cite journal | author = Danesh J, Collins R, Peto R | title = Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies | journal = Circulation | volume = 102 | issue = 10 | pages = 1082–5 | year = 2000 | pmid = 10973834 | doi = | issn = | url = http://circ.ahajournals.org/cgi/content/abstract/102/10/1082 ] 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.cite journal | author = Berglund L, Ramakrishnan R | title = Lipoprotein(a): an elusive cardiovascular risk factor | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 24 | issue = 12 | pages = 2219–26 | year = 2004 | pmid = 15345512 | doi = 10.1161/01.ATV.0000144010.55563.63 | issn = ] Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter.cite journal | author = Klausen IC, Sjøl A, Hansen PS, Gerdes LU, Møller L, Lemming L, Schroll M, Faergeman O | title = Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study | journal = Atherosclerosis | volume = 132 | issue = 1 | pages = 77–84 | year = 1997 | pmid = 9247362 | doi = 10.1016/S0021-9150(97)00071-3 | issn = ] cite journal | author = Paultre F, Pearson TA, Weil HF, Tuck CH, Myerson M, Rubin J, Francis CK, Marx HF, Philbin EF, Reed RG, Berglund L | title = High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 20 | issue = 12 | pages = 2619–24 | year = 2000 | pmid = 11116062 | doi = | issn = | url = http://atvb.ahajournals.org/cgi/content/abstract/20/12/2619 ] Furthermore, the ethnic origin of an individual must be considered when evaluating its Lp(a) concentration in respect of the risk for cardiovascular events.cite journal | author = Dahlén GH, Ekstedt B | title = The importance of the relation between lipoprotein(a) and lipids for development of atherosclerosis and cardiovascular disease | journal = J. Intern. Med. | volume = 250 | issue = 3 | pages = 265–7 | year = 2001 | pmid = 11555135 | doi = 10.1046/j.1365-2796.2001.00889.x | issn = ] [G. H. Dahlen and B. Ekstedt, J.Intern.Med 250, 265-267 (2001)] 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.cite journal | author = Helmhold M, Bigge J, Muche R, Mainoo J, Thiery J, Seidel D, Armstrong VW | title = Contribution of the apo [a] phenotype to plasma Lp(a) concentrations shows considerable ethnic variation | journal = J. Lipid Res. | volume = 32 | issue = 12 | pages = 1919–28 | year = 1991 | pmid = 1840066 | doi = | issn = | url = http://www.jlr.org/cgi/content/abstract/32/12/1919] cite journal | author = Cobbaert C, Mulder P, Lindemans J, Kesteloot H | title = Serum LP(a) levels in African aboriginal Pygmies and Bantus, compared with Caucasian and Asian population samples | journal = J Clin Epidemiol | volume = 50 | issue = 9 | pages = 1045–53 | year = 1997 | pmid = 9363039 | doi = 10.1016/S0895-4356(97)00129-7 | issn = ] cite journal | author = Schmidt K, Kraft HG, Parson W, Utermann G | title = Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon | journal = Eur. J. Hum. Genet. | volume = 14 | issue = 2 | pages = 190–201 | year = 2006 | pmid = 16267501 | doi = 10.1038/sj.ejhg.5201512 | issn = ] Furthermore, Lp(a) measurement is in urgent need of standardisation.cite journal | author = Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, Sakurabayashi I, Tate JR, Steinmetz A | title = 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) | journal = Clin. Chem. | volume = 46 | issue = 12 | pages = 1956–67 | year = 2000 | pmid = 11106328 | doi = | issn = | url = http://www.clinchem.org/cgi/content/abstract/46/12/1956 ]

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

Lipoprotein(a) - Lp(a)cite book | author = Ryan, George M; Julius Torelli | title = Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you | publisher = St. Martin's Griffin | location = New York | year = 2005 | pages = page 91 | isbn = 0-312-34863-0 | oclc = | doi = ] : Desirable: < 14 mg/dL (< 35 nmol/l): Borderline risk: 14 - 30 mg/dL (35 - 75 nmol/l): High risk: 31 - 50 mg/dL (75 - 125 nmol/l): Very high risk: > 50 mg/dL (> 125 nmol/l)

ee also

* Lipoprotein
* Apolipoprotein
* Very low density lipoprotein
* Low density lipoprotein
* Combined hyperlipidemia

References

Further reading

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

External links

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