Dullaart, Robin P. F.

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University of Groningen

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. [dgz111]. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

Lipoprotein(a):The Renaissance of an Enigmatic Lipoprotein

Dissertations of the University of Groningen

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. [dgz111]. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-06-2022e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

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Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein

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   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. Article dgz111. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-09-2023e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

Proceedings - University of Groningen

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. [dgz111]. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 04-06-2022e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. [dgz111]. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 19-11-2022e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. Article dgz111. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–627. 13. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipo-protein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49(10):2230–2239. 14. Dullaart  RP, van  Doormaal  JJ, Hoogenberg  K, Sluiter  WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypo-thyroid subjects. Neth J Med. 1995;46(4):179–184. 15. Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thy-roid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–916. 16. Beentjes  JA, van  Tol  A, Sluiter  WJ, Dullaart  RP. Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. Atherosclerosis. 2000;153(2):491–498. 17. Beentjes JA, van Tol A, Sluiter WJ, Dullaart RP. Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults. J Lipid Res. 2000;41(6):925–932. 18. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. 19. Reyes-Soffer  G, Ginsberg  HN, Ramakrishnan  R. The metab-olism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58(9):1756–1764. 20. Ma  L, Chan  DC, Ooi  EMM, Marcovina  SM, Barrett  PHR, Watts  GF. Apolipoprotein(a) kinetics in statin-treated pa-tients with elevated plasma lipoprotein(a) concentration. J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-01382. 21. Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with ele-vated and normal Lp(a) concentration. Metabolism. 2019;96:8–11. 22. Rader DJ, Cain W, Ikewaki K, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to dif-ferences in production rate. J Clin Invest. 1994;93(6):2758–2763. 23. Ray  KK, Vallejo-Vaz  AJ, Ginsberg  HN, et  al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardio-vascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202.e898  Dullaart  Lipoprotein(a)  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020

   University of GroningenLipoprotein(a)Dullaart, Robin P. F.Published in:Journal of Clinical Endocrinology & MetabolismDOI:10.1210/clinem/dgz111IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2020Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Dullaart, R. P. F. (2020). Lipoprotein(a): The Renaissance of an Enigmatic Lipoprotein. Journal of ClinicalEndocrinology & Metabolism, 105(3), E896-E898. Article dgz111. https://doi.org/10.1210/clinem/dgz111CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 01-11-2023e896  J Clin Endocrinol Metab, March 2020, 105(3):e896–e898  https://academic.oup.com/jcem doi:10.1210/clinem/dgz111ISSN Print 0021-972X ISSN Online 1945-7197Printed in USA© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comReceived 8 August 2019. Accepted 8 October 2019.First Published Online 23 October 2019.Corrected and Typeset 20 February 2020. C O M M E N T A R YLipoprotein(a): The Renaissance of an Enigmatic LipoproteinRobin P. F. DullaartDepartment of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The NetherlandsORCiD number: 0000-0003-4520-1239 (Robin P. F. Dullaart).Key Words: apolipoprotein(a), apolipoprotein(a) production rate, lipoprotein(a), LPA gene, cardiovascular diseaseHuman plasma contains lipoprotein(a) [Lp(a)], a macromolecular complex that consists of a low density lipoprotein (LDL) particle to which a glyco-protein, known as apolipoprotein (a) [apo(a)], is linked via a disulfide bond to apolipoprotein B100 (apoB100), the principal protein that is carried on LDL particles (1, 2). Ever since the discovery of this lipoprotein in 1963 by Kåre Berg (3), Lp(a) has intrigued clinicians and researchers because of its complex genetics and its enigmatic regulation.Similar to plasminogen, apo(a) contains loop-like structures, called kringles (4). Besides kringle IV-1 (KIV-1), human apo(a) contains KIV-2 to KIV-10, KV and a probably inactive protease domain (4). Apo(a) is highly heterogeneous in size. Smaller apo(a) isoforms are associ-ated with higher plasma levels of Lp(a). Variable numbers of tandemly repeated exon sequences in the LPA locus (chromosome 6q2.6-q2.7) encoding KIV-2 of apo(a), a form of copy number variation (CNV), give rise to con-siderable size polymorphism of the apo(a) protein (4). The circulating level of Lp(a) is strongly and inversely de-termined by the KIV-2 copy number in apo(a), explaining to a considerable extent the marked variation in plasma Lp(a) levels between individuals (1, 4). Lp(a) also varies between individuals of different ethnicities with people of black ethnicity generally having higher levels than people of white and Asian ethnicity (1, 4). In humans, Lp(a) is predominantly, if not exclusively produced, by the liver (4). The process of Lp(a) assembly and release in the cir-culation is not precisely known, but involves covalent binding of apo(a) to apoB100 via the formation of a disul-fide bridge between these protein moieties (4). However, it is unclear whether Lp(a) assembly is primarily an intra-cellular event or takes places at the surface of hepatocytes or even in the extracellular space. Nonetheless, while very low density lipoproteins (VLDLs) are considered precursors of LDLs, there is virtually no correlation of VLDL-apoB100 nor of LDL-apoB100 production with apo(a) production (5), suggesting that apoB100 and apo(a) influx in the extracellular compartment are to a considerable extent unrelated processes. Furthermore, the molecular mechanisms responsible for Lp(a) catabolism still remain elusive, although the catabolism apo(a) and apoB100 in Lp(a) particles are tightly coupled. Several re-ceptor systems that include lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen recep-tors have been proposed to be implicated in Lp(a) ca-tabolism (6). Of interest, the toll-like receptor-2 was the only receptor that was associated with Lp(a) in a genome wide association study (6). The importance of the LDL receptor for Lp(a) catabolism has not yet been fully eluci-dated (1, 4). Plasma Lp(a) is clearly elevated in some pa-tients with heterozygous familial hypercholesterolemia in the context of certain dysfunctional variants in the LDLR gene encoding the LDL receptor, in the APOB gene that alter apoB-100 receptor binding, and in gain-of-function Abbreviations: apo(a), apolipoprotein(a); apoB100, apolipoprotein B100; CNV, copy number variation; CVD, cardiovascular disease; GH, growth hormone; HDL, high dens-ity lipoprotein; KIV, kringle IV; LDL, low density lipoprotein; Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low density lipoprotein.NList_dot_numeric1Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020mutations in PCSK9 encoding proprotein convertase subtilisin/kexin type 9 (7, 8). By contrast, statins, which act by increasing LDL receptor availability on the surface of hepatocytes, do not lower but—on the contrary—may even increase plasma Lp(a) (9).A large body of evidence has now been accumu-lated to indicate that high plasma Lp(a) is associated with increased risk of newly developed and recurrent atherosclerotic cardiovascular disease (CVD) events [reviewed in (1, 2)]. Of further note, Mendelian ran-domization studies have evaluated several forms of genomic variation in LPA, including single nucleotide polymorphisms (SNPs) and CNV in the KIV-2 coding sequence, and have shown that both types of variation on LPA are causally related to atherosclerotic CVD in individuals of various ethnicities tested (10–12). In fact, variation in LPA is considered to represent the single strongest lipid genetic risk factor for CVD (1).Apo(a) immunoreactivity is detectable in atheroscler-otic plaques. Several pro-atherogenic mechanisms of Lp(a) have been proposed (1, 4). However, the extent to which Lp(a) may interfere with clotting and fibrinolytic actions in vivo is not well known. Importantly, Lp(a) is the preferred lipoprotein carrier of oxidized phospho-lipids, suggesting a mechanism whereby Lp(a) may pro-mote pro-inflammatory pathways in the arterial wall (13). Interestingly, oxidized phospholipids on apoB100 associate with LPA variants, underscoring the idea that oxidized phospholipids form part of the process whereby Lp(a) exerts its pro-atherogenic properties (11).Besides the paramount contribution of genetic variation in LPA, Lp(a) is also subject to hormonal regulation (1). Lp(a) levels are increased in overt hypothyroidism (1) and are rapidly lowered after tri-iodothyronine supplementation in individuals with profound hypothyroidism (14). An Lp(a)-decreasing ef-fect has also been found in response to thyromimetics (15). There are no major sex differences in Lp(a), but its level is higher in postmenopausal vs premenopausal women. Estrogens and androgens may both decrease Lp(a) (1). Levels of Lp(a) are increased in the context of acromegaly (1, 16). Likewise, Lp(a) may increase in response to growth hormone growth hormone (GH) ad-ministration in GH-deficient adults, an effect which is opposite of the decrease in LDL cholesterol and non-high density lipoprotein (non-HDL) cholesterol (1, 17). Intriguingly, lower Lp(a) levels may confer increased risk of developing type 2 diabetes (18). Plasma Lp(a) is also elevated in chronic kidney disease, as well as in the nephrotic syndrome (1)In order to improve the rationale for Lp(a) targeted ther-apies it is important to discern mechanisms responsible for its regulation. One valuable approach is to apply stable isotope kinetic modelling to interrogate Lp(a) metabolism (19). Such techniques are methodologically difficult and are critically dependent on the isolation of Lp(a), required to be devoid of other lipoproteins that contain apoB (19). Moreover among other uncertainties, the mathematics of the kinetic model applied are dependent on the assumption as to whether apo(a) is recycled in the circulation (19). In a recent issue of JCEM, Ma et al report on apo(a) kinetics in patients at high CVD risk who are receiving statin therapy (20). Using labor intensive stable isotope methodology and isolation of apo(a) by immunoprecipitation followed by sodium dodecyl sulfate gel electrophoresis and Western blotting, they showed that the production rate of apo(a) is increased in subjects with elevated plasma Lp(a) compared with individuals who have normal levels of Lp(a). Notably, no difference in apo(a) fractional catabolic rate between the high and low Lp(a) groups was found (20). In another re-cent study among statin-treated subjects, the same research group reported that the apo(a) fractional catabolic rate was similar compared with that of apoB, irrespective of whether plasma Lp(a) was elevated (21). In comparison, an early re-port by Rader et al in which Lp(a) was labelled with radio-active iodine revealed a strong correlation of plasma Lp(a) with its production rate but not with its fractional catabolic rate among healthy young adults (22).Thus for many reasons, Lp(a) has regained interest as CVD risk biomarker. Lp(a) measurement may be useful to improve CVD risk classification in selected patients, including those who have suffered a recurrent event (2). Notwithstanding the modest decrease of Lp(a) in re-sponse to PCSK9 inhibitor treatment (23), there remains an unmet need to reduce Lp(a) in high-risk patients in whom it is elevated. Evidence is accumulating in support of the possibility that increased plasma Lp(a) concentra-tions, which coincide with smaller-sized apo(a) isoforms, are primarily due to increased hepatic production. These findings provide a rationale to develop Lp(a)-targeted therapies directed toward inhibition of its synthesis. Treatment based on antisense technology is currently being tested, but its efficacy and safety still have to be proven in CVD outcome studies. It is hoped that such treatment will reach the clinic in the near future.Additional InformationCorrespondence: Robin P.  F. Dullaart, MD, PhD, Department of Endocrinology, University Medical Center Groningen, Groningen, P.O. Box 3001, 9700 RB Groningen, The Netherlands; E-mail: r.p.f.dullaart@umcg.nl.Disclosure Summary: The author has nothing to disclose.doi:10.1210/clinem/dgz111 https://academic.oup.com/jcem  e897Downloaded from https://academic.oup.com/jcem/article/105/3/e896/5602695 by University of Groningen user on 24 September 2020Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.References 1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by gen-etics. J Intern Med. 2013;273(1):6–30. 2. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J. 2017;38(20):1553–1560. 3. Berg K. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand. 1963;59:369–382. 4. Schmidt  K, Noureen  A, Kronenberg  F, Utermann  G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–1359. 5. Chan  DC, Watts  GF, Coll  B, Wasserman  SM, Marcovina  SM, Barrett  PHR. Lipoprotein(a) particle production as a deter-minant of plasma lipoprotein(a) concentration across varying apolipoprotein(a) isoform sizes and background cholesterol-lowering therapy. J Am Heart Assoc. 2019;8(7):e011781. 6. McCormick  SPA, Schneider  WJ. Lipoprotein(a) catabolism: a case of multiple receptors. Pathology. 2019;51(2):155–164. 7. Tada  H, Kawashiri  MA, Yoshida  T, et  al. Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) gain-of-function mutations. Circ J. 2016;80(2):512–518. 8. Sjouke  B, Yahya  R, Tanck  MWT, et  al. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hyper-cholesterolemia. J Clin Lipidol. 2017;11(2):507–514. 9. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2019. doi: 10.1093/eurheartj/ehz310. 10. Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and cor-onary disease. N Engl J Med. 2009;361(26):2518–2528. 11. Saleheen  D, Haycock  PC, Zhao  W, et  al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5(7):524–533. 12. Burgess  S, Ference  BA, Staley  JR, et  al.; European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium. 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Lipoprotein(a):The Renaissance of an Enigmatic Lipoprotein

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