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The metabolism of lipoprotein (a): an ever-evolving story

2017; Elsevier BV; Volume: 58; Issue: 9 Linguagem: Inglês

10.1194/jlr.r077693

ISSN

1539-7262

Autores

Gissette Reyes‐Soffer, Henry N. Ginsberg, Rajasekhar Ramakrishnan,

Tópico(s)

Atherosclerosis and Cardiovascular Diseases

Resumo

Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) (LPA) was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism. Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) (LPA) was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism. Lipoprotein (a) [Lp(a)] is characterized by apo(a) covalently bound to apoB-100. It was described in human plasma by Berg in 1963 (1.Berg K. A new serum type system in man-the LP system.Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Crossref PubMed Scopus (1040) Google Scholar, 2.Witztum J.L. Ginsberg H.N. Lipoprotein (a): coming of age at last.J. Lipid Res. 2016; 57: 336-339Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). The human gene encoding apo(a) (LPA), located on chromosome 6q26-27, was cloned in 1987 by Lawn and colleagues (3.McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Scopus (1590) Google Scholar). Lp(a) plasma concentrations are genetically determined by the LPA gene (4.Boerwinkle E. Leffert C.C. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (821) Google Scholar), with 30–70% (5.Utermann G. Genetic architecture and evolution of the lipoprotein(a) trait.Curr. Opin. Lipidol. 1999; 10: 133-141Crossref PubMed Scopus (80) Google Scholar) of the variability of plasma levels due to differences in the number of repeats in the DNA sequence encoding kringle IV type 2 (KIV-2). This results in a spectrum of circulating apo(a) protein isoforms from 1 to >40 KIV-2 repeats (3.McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Scopus (1590) Google Scholar, 6.Utermann G. Menzel H.J. Kraft H.G. Duba H.C. Kemmler H.G. Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.J. Clin. Invest. 1987; 80: 458-465Crossref PubMed Scopus (725) Google Scholar, 7.Sandholzer C. Hallman D.M. Saha N. Sigurdsson G. Lackner C. Császár A. Boerwinkle E. Utermann G. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups.Hum. Genet. 1991; 86: 607-614Crossref PubMed Scopus (349) Google Scholar, 8.Schmidt K. Noureen A. Kronenberg F. Utermann G. Structure, function, and genetics of lipoprotein (a).J. Lipid Res. 2016; 57: 1339-1359Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 9.Enkhmaa B. Anuurad E. Zhang W. Tran T. Berglund L. Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk.Metab. Syndr. Relat. Disord. 2011; 9: 411-418Crossref PubMed Scopus (28) Google Scholar) and a corresponding range of molecular masses that has been estimated to range from 300 to 800 kDa. There is an inverse relationship between the size of the apo(a) isoforms and Lp(a) plasma concentration. Additionally, sequence variants in LPA play a significant role in determining plasma Lp(a) levels (4.Boerwinkle E. Leffert C.C. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (821) Google Scholar). Large epidemiologic studies show a strong link between increases in Lp(a) plasma levels and risk of atherosclerotic cardiovascular disease (9.Enkhmaa B. Anuurad E. Zhang W. Tran T. Berglund L. Lipoprotein(a): genotype-phenotype relationship and impact on atherogenic risk.Metab. Syndr. Relat. Disord. 2011; 9: 411-418Crossref PubMed Scopus (28) Google Scholar, 10.Danesh J. Collins R. Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.Circulation. 2000; 102: 1082-1085Crossref PubMed Scopus (814) Google Scholar, 11.Wilde C. LP (a) risk factor # IV, inherited.in: Hidden Causesof Heart Attack and Stroke: Inflammation, Cardiology's New Frontier. Abigon Press, Studio City, CA2003: 182-183Google Scholar, 12.Emerging Risk Factors Collaboration Erqou S. Kaptoge S. Perry P.L. Di Angelantonio E. Thompson A. White I.R. Marcovina S.M. Collins R. et al.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.JAMA. 2009; 302: 412-423Crossref PubMed Scopus (1145) Google Scholar), and Lp(a) is present in human atheroma (13.Pepin J.M. O'Neil J.A. Hoff H.F. Quantification of apo[a] and apoB in human atherosclerotic lesions.J. Lipid Res. 1991; 32: 317-327Abstract Full Text PDF PubMed Google Scholar, 14.Hoff H.F. O'Neil J. Yashiro A. Partial characterization of lipoproteins containing apo[a] in human atherosclerotic lesions.J. Lipid Res. 1993; 34: 789-798Abstract Full Text PDF PubMed Google Scholar). More recently, genetic studies, including Mendelian randomization approaches, have provided convincing evidence that LPA is associated causally with coronary heart disease and the development of aortic stenosis (15.Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S.C. Parish S. Barlera S. Franzosi M.G. Rust S. et al.Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1018) Google Scholar, 16.Afshar M. Kamstrup P.R. Williams K. Sniderman A.D. Nordestgaard B.G. Thanassoulis G. Estimating the population impact of Lp(a) lowering on the incidence of myocardial infarction and aortic stenosis-brief report.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 2421-2423Crossref PubMed Scopus (28) Google Scholar, 17.Nordestgaard B.G. Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.J. Lipid Res. 2016; 57: 1953-1975Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 18.Saleheen D. Haycock P.C. Zhao W. Rasheed A. Taleb A. Imran A. Abbas S. Majeed F. Akhtar S. Qamar N. et al.Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a Mendelian randomisation analysis.Lancet Diabetes Endocrinol. 2017; 5: 524-533Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 19.Thanassoulis G. Campbell C.Y. Owens D.S. Smith J.G. Smith A.V. Peloso G.M. Kerr K.F. Pechlivanis S. Budoff M.J. Harris T.B. CHARGE Extracoronary Calcium Working Group et al.Genetic associations with valvular calcification and aortic stenosis.N. Engl. J. Med. 2013; 368: 503-512Crossref PubMed Scopus (616) Google Scholar). Despite all that is known about the LPA gene and the structure of circulating Lp(a) (4.Boerwinkle E. Leffert C.C. Lin J. Lackner C. Chiesa G. Hobbs H.H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (821) Google Scholar), there is much uncertainty regarding the site(s) of the assembly and production of Lp(a), the stability of the bond between apo(a) and apoB in plasma, and the site(s) of Lp(a) clearance and degradation. Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which class of apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether the binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and whether Lp(a) or apo(a) leave the circulation via the LDL receptor pathway (20.Dieplinger H. Utermann G. The seventh myth of lipoprotein(a): where and how is it assembled?.Curr. Opin. Lipidol. 1999; 10: 275-283Crossref PubMed Scopus (36) Google Scholar, 21.Koschinsky M.L. Marcovina S.M. Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity.Curr. Opin. Lipidol. 2004; 15: 167-174Crossref PubMed Scopus (114) Google Scholar, 22.Sharma M. Redpath G.M. Williams M.J.A. McCormick S.P.A. Recycling of apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a).Circ. Res. 2017; 120: 1091-1102Crossref PubMed Scopus (48) Google Scholar) or through other potential pathways (22.Sharma M. Redpath G.M. Williams M.J.A. McCormick S.P.A. Recycling of apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a).Circ. Res. 2017; 120: 1091-1102Crossref PubMed Scopus (48) Google Scholar, 23.Lamon-Fava S. Diffenderfer M.R. Marcovina S.M. Lipoprotein(a) metabolism.Curr. Opin. Lipidol. 2014; 25: 189-193Crossref PubMed Scopus (38) Google Scholar). The difficulties inherent in understanding Lp(a) metabolism have been previously reviewed by various investigators including Dieplinger (24.Dieplinger H. Lipoprotein(a): the really bad cholesterol?.Biochem. Soc. Trans. 1999; 27: 439-447Crossref PubMed Scopus (3) Google Scholar) in 1999 and more recently by Hoover-Plow and Huang (25.Hoover-Plow J. Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets.Metabolism. 2013; 62: 479-491Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar) and Lamon-Fava, Diffenderfer, and Marcovina (23.Lamon-Fava S. Diffenderfer M.R. Marcovina S.M. Lipoprotein(a) metabolism.Curr. Opin. Lipidol. 2014; 25: 189-193Crossref PubMed Scopus (38) Google Scholar). Importantly, comparison of available in vivo metabolic studies is confounded by the different approaches to isolating Lp(a), different labeling techniques, and different dietary and sampling protocols that have been used. Due to the difficulty in studying Lp(a) metabolism, each original research report described in the present review also includes an in-depth examination of the relevant literature available to the investigators at the time of their study. This review will focus on the past, current, and future use of stable isotopes in the study of Lp(a) metabolism, highlighting critical metabolic uncertainties that exist. It is well established that the apo(a) and apoB components of Lp(a) are assembled in the liver. Most studies in cultured hepatocytes indicate that binding of apo(a) and apoB to form Lp(a) occurs either at the surface of the hepatocyte or in the media (which represents the extracellular space in vivo), rather than in the intracellular secretory pathway (26.White A.L. Rainwater D.L. Hixson J.E. Estlack L.E. Lanford R.E. Intracellular processing of apo(a) in primary baboon hepatocytes.Chem. Phys. Lipids. 1994; 67–68: 123-133Crossref PubMed Scopus (29) Google Scholar, 27.Lobentanz E.M. Krasznai K. Gruber A. Brunner C. Muller H.J. Sattler J. Kraft H.G. Utermann G. Dieplinger H. Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.Biochemistry. 1998; 37: 5417-5425Crossref PubMed Scopus (44) Google Scholar), with the number of KIV-2 repeats determining the proportion of newly synthesized apo(a) that is secreted rather than degraded intracellularly, possibly by the proteasome (27.Lobentanz E.M. Krasznai K. Gruber A. Brunner C. Muller H.J. Sattler J. Kraft H.G. Utermann G. Dieplinger H. Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.Biochemistry. 1998; 37: 5417-5425Crossref PubMed Scopus (44) Google Scholar). On the other hand, there are studies in cultured cells supporting intracellular assembly of Lp(a) (28.Bonen D.K. Hausman A.M. Hadjiagapiou C. Skarosi S.F. Davidson N.O. Expression of a recombinant apolipoprotein(a) in HepG2 cells. Evidence for intracellular assembly of lipoprotein(a).J. Biol. Chem. 1997; 272: 5659-5667Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 29.Edelstein C. Davidson N.O. Scanu A.M. Oleate stimulates the formation of triglyceride-rich particles containing apoB100-apo(a) in long-term primary cultures of human hepatocytes.Chem. Phys. Lipids. 1994; 67–68: 135-143Crossref PubMed Scopus (43) Google Scholar).There is also evidence supporting a role for translational efficiency of apo(a) mRNA in the regulation of apo(a) production (30.Zysow B.R. Lindahl G.E. Wade D.P. Knight B.L. Lawn R.M. C/T polymorphism in the 5′ untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 58-64Crossref PubMed Scopus (101) Google Scholar). From the authors'n perspective, studies in cultured cells support a model where the assembly of Lp(a) occurs on the surface of the liver or in an extra-hepatic space separated from plasma. In contrast to the cellular data, three early in vivo stable isotope studies in humans, by Gaubatz et al. (31.Gaubatz J.W. Nava M.N. Guyton J.R. Hoffman A.S. Opekun A.R. Hachey D.L. Morrisett J.D. Metabolism of apo(a) and apoB-100 in human lipoprotein(a).in: Catapano A.L. Gotto Jr., A.M. Smith L.C. Drugs Affecting Lipid Metabolism. Springer, Dordrecht, The Netherlands1993: 161-167Crossref Google Scholar), Su et al. (32.Su W. Campos H. Judge H. Walsh B.W. Sacks F.M. Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement.J. Clin. Endocrinol. Metab. 1998; 83: 3267-3276Crossref PubMed Scopus (65) Google Scholar), and Frischmann et al. (33.Frischmann M.E. Ikewaki K. Trenkwalder E. Lamina C. Dieplinger B. Soufi M. Schweer H. Schaefer J.R. Konig P. Kronenberg F. et al.In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a).Atherosclerosis. 2012; 225: 322-327Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), provided support for the intracellular assembly of Lp(a). All of these studies used deuterated amino acids, but isolated Lp(a), apo(a), and apoB in Lp(a) by different methods. Importantly, they all observed similar rates of enrichment of plasma Lp(a)-apo(a) and Lp(a)-apoB and determined the fractional clearance rates (FCRs) for both moieties of Lp(a) to be about 0.25 pool/day, lower than that of LDL-apoB (which ranges from 0.3 to 0.5 pool/day). Although these data did not rule out assembly of Lp(a) from its components at sites on the surface of hepatocytes protected from circulating LDL, they argued strongly against the fusion of circulating free apo(a) with circulating apoB particles. However, Demant et al. (34.Demant T. Seeberg K. Bedynek A. Seidel D. The metabolism of lipoprotein(a) and other apolipoprotein B-containing lipoproteins: a kinetic study in humans.Atherosclerosis. 2001; 157: 325-339Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) observed differences in the rise in enrichment of Lp(a)-apo(a) and Lp(a)-apoB and, using a more complex compartmental model to analyze their data, reported that about one-half of Lp(a) was assembled in the liver and one-half in plasma, where free apo(a) combined with circulating IDL and LDL. In vivo studies in genetically manipulated mice support both intracellular and extracellular assembly of Lp(a). Thus, crossing apo(a) transgenic mice with apoB transgenic mice resulted in the appearance of mature Lp(a) in the circulation concomitant with the disappearance of free apo(a) that was present in apo(a) transgenic mice, supporting the intracellular assembly of Lp(a) (35.Chiesa G. Hobbs H.H. Koschinsky M.L. Lawn R.M. Maika S.D. Hammer R.E. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a).J. Biol. Chem. 1992; 267: 24369-24374Abstract Full Text PDF PubMed Google Scholar). In contrast, infusion of human LDL-apoB into mice transgenic for human apo(a) generated Lp(a) from circulating free apo(a), albeit under very nonphysiological conditions (36.Linton M.F. Farese Jr., R.V. Chiesa G. Grass D.S. Chin P. Hammer R.E. Hobbs H.H. Young S.G. Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein (a).J. Clin. Invest. 1993; 92: 3029-3037Crossref PubMed Scopus (211) Google Scholar). From the authors'n perspective, at the present time, in vivo studies of Lp(a) kinetics in humans support assembly of Lp(a) within the liver, at the surface of the liver, or in an extra-hepatic space separated from plasma. If Lp(a) is assembled within the liver, at the surface of the liver, or just outside the liver in a "protected" space from which circulating LDL-apoB is excluded, which apoB-100 lipoprotein is involved? Because VLDL is the major apoB-100 lipoprotein secreted from the liver, several groups have examined the binding of apo(a) to VLDL or the presence of Lp(a) among lipoproteins isolated in the d < 1.006 range. The consensus of these studies is that, in vitro, apo(a) can bind to a range of lipoproteins (37.Pfaffinger D. Schuelke J. Kim C. Scanu A.M. Relationship between apo[a] isoforms and Lp[a] density in subjects with different apo[a] phenotype: a study before and after a fatty meal.J. Lipid Res. 1991; 32: 679-683Abstract Full Text PDF PubMed Google Scholar) and that, in vivo, Lp(a) can be isolated from the d < 1.006 range in plasma of hypertriglyceridemic subjects and of individuals with normal fasting triglycerides (TGs) after they have ingested a high fat meal (37.Pfaffinger D. Schuelke J. Kim C. Scanu A.M. Relationship between apo[a] isoforms and Lp[a] density in subjects with different apo[a] phenotype: a study before and after a fatty meal.J. Lipid Res. 1991; 32: 679-683Abstract Full Text PDF PubMed Google Scholar, 38.Ooi E.M. Watts G.F. Chan D.C. Pang J. Tenneti V.S. Hamilton S.J. McCormick S.P. Marcovina S.M. Barrett P.H. Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 2686-2693Crossref PubMed Scopus (42) Google Scholar, 39.McConathy W.J. Trieu V.N. Koren E. Wang C.S. Corder C.C. Triglyceride-rich lipoprotein interactions with Lp(a).Chem. Phys. Lipids. 1994; 67–68: 105-113Crossref PubMed Scopus (20) Google Scholar, 40.Bersot T.P. Innerarity T.L. Pitas R.E. Rall Jr., S.C. Weisgraber K.H. Mahley R.W. Fat feeding in humans induces lipoproteins of density less than 1.006 that are enriched in apolipoprotein (a) and that cause lipid accumulation in macrophages.J. Clin. Invest. 1986; 77: 622-630Crossref PubMed Scopus (90) Google Scholar). However, Krempler et al. (41.Krempler F. Kostner G. Bolzano K. Sandhofer F. Lipoprotein (a) is not a metabolic product of other lipoproteins containing apolipoprotein B.Biochim. Biophys. Acta. 1979; 575: 63-70Crossref PubMed Scopus (67) Google Scholar) found no evidence of a precursor-product relationship between VLDL or LDL and Lp(a) after injection of radiolabeled VLDL into normal subjects. In addition, when VLDL was infused into apo(a) transgenic mice, the appearance of circulating Lp(a) was significantly delayed compared with the infusion of LDL (35.Chiesa G. Hobbs H.H. Koschinsky M.L. Lawn R.M. Maika S.D. Hammer R.E. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a).J. Biol. Chem. 1992; 267: 24369-24374Abstract Full Text PDF PubMed Google Scholar). If VLDL is not the lipoprotein to which apo(a) initially binds, then the nascent Lp(a) must arise from the binding of apo(a) to smaller apoB particles (IDL and/or LDL) and, if this does not occur in the circulation, the liver must be secreting one or both of these Lp(a) particle sizes. In fact, direct production of LDL-apoB has been observed in numerous human lipoprotein kinetic studies utilizing both exogenous and endogenous labeling approaches (42.Parhofer K.G. Barrett H.R. What we have learned about VLDL and LDL metabolism from human kinetics studies.J. Lipid Res. 2006; 47: 1620-1630Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 43.Ginsberg H.N. Le N.A. Short M.P. Ramakrishnan R. Desnick R.J. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis.J. Clin. Invest. 1987; 80: 1692-1697Crossref PubMed Scopus (159) Google Scholar, 43.Reyes-Soffer G. Moon B. Hernandez-Ono A. Dionizovik-Dimanovski M. Jimenez J. Obunike J. Thomas T. Ngai C. Fontanez N. Donovan D.S. et al.Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans.Sci. Transl. Med. 2016; 8: 323ra12Crossref PubMed Scopus (24) Google Scholar). Those studies did not, however, examine Lp(a)-apo(a) and Lp(a)-apoB metabolism at the same time. We have unpublished data indicating that Lp(a) isolated at the density of VLDL and IDL (d < 1.019) has the same FCR as Lp(a) in the density range of LDL/HDL. Because the pool size of Lp(a) in the d < 1.019 fraction is very small, it cannot have the same FCR of the much larger pool of Lp(a) in the LDL/HDL density range and also be the precursor of the latter. From the authors'n perspective, based on available data, the majority of Lp(a) must enter the circulation as a particle with a density greater than 1.019. The earliest reported kinetic studies by Krempler and colleagues (44.Krempler F. Kostner G.M. Bolzano K. Sandhofer F. Turnover of lipoprotein (a) in man.J. Clin. Invest. 1980; 65: 1483-1490Crossref PubMed Scopus (217) Google Scholar, 45.Krempler F. Kostner G.M. Roscher A. Haslauer F. Bolzano K. Sandhofer F. Studies on the role of specific cell surface receptors in the removal of in man.J. Clin. Invest. 1983; 71: 1431-1441Crossref PubMed Scopus (154) Google Scholar) used radio-iodinated Lp(a) and found that the FCR for Lp(a) in normal subjects was 0.3 pool/day. They demonstrated equivalent decay curves for serum, purified Lp(a), and the fractionated protein components of Lp(a), indicative of equal clearance rates of Lp(a)-apo(a) and Lp(a)-apoB. However, Knight et al. (46.Knight B.L. Perombelon Y.F. Soutar A.K. Wade D.P. Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.Atherosclerosis. 1991; 87: 227-237Abstract Full Text PDF PubMed Scopus (83) Google Scholar), using radiolabeled Lp(a) isolated by a different method than used by Krempler, observed dissociation and rapid clearance of the Lp(a)-apo(a) originally bound to Lp(a)-apoB, with the generation of an LDL-like particle in plasma of normal subjects and individuals with familial hypercholesterolemia (FH). Knight'ns result must be viewed with caution, as there is no evidence for a "significant" pool of free apo(a) in the circulation and, if dissolution of the apo(a)-apoB complex in Lp(a) was followed by rapid clearance of free apo(a) [leaving behind an LDL, as suggested by Knight et al. (46.Knight B.L. Perombelon Y.F. Soutar A.K. Wade D.P. Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.Atherosclerosis. 1991; 87: 227-237Abstract Full Text PDF PubMed Scopus (83) Google Scholar)], the FCR of that "Lp(a)," which would essentially be an LDL labeled in apoB, would be similar to the FCR of radiolabeled LDL in normal subjects that Knight et al. (46.Knight B.L. Perombelon Y.F. Soutar A.K. Wade D.P. Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.Atherosclerosis. 1991; 87: 227-237Abstract Full Text PDF PubMed Scopus (83) Google Scholar) studied simultaneously. As noted above, Demant et al. (34.Demant T. Seeberg K. Bedynek A. Seidel D. The metabolism of lipoprotein(a) and other apolipoprotein B-containing lipoproteins: a kinetic study in humans.Atherosclerosis. 2001; 157: 325-339Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), using stable isotopes, found that the FCRs for Lp(a)-apo(a) and Lp(a)-apoB were similar, indicating that, independent of the site of formation of Lp(a), Lp(a)-apo(a) and Lp(a)-apoB remained linked until they left the circulation together and were degraded. The results of this study have been replicated recently (33.Frischmann M.E. Ikewaki K. Trenkwalder E. Lamina C. Dieplinger B. Soufi M. Schweer H. Schaefer J.R. Konig P. Kronenberg F. et al.In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a).Atherosclerosis. 2012; 225: 322-327Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Two additional studies from one group, using stable isotopes, found differences in the rates of enrichment of Lp(a)-apo(a) and Lp(a)-apoB. In the first, Jenner et al. (47.Jenner J.L. Seman L.J. Millar J.S. Lamon-Fava S. Welty F.K. Dolnikowski G.G. Marcovina S.M. Lichtenstein A.H. Barrett P.H. deLuca C. et al.The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings.Metabolism. 2005; 54: 361-369Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) used a lectin-based isolation method and found FCRs of 0.22 and 0.46 pool/day for Lp(a)-apo(a) and Lp(a)-apoB, respectively. In the second study, Diffenderfer et al. (48.Diffenderfer M.R. Lamon-Fava S. Marcovina S.M. Barrett P.H. Lel J. Dolnikowski G.G. Berglund L. Schaefer E.J. Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a).Metabolism. 2016; 65: 381-390Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar) used immunoprecipitation of Lp(a) from plasma and reported FCRs of 0.10 and 0.26 pool/day for Lp(a)-apo(a) and Lp(a)-apoB-100. The results of these two studies are incompatible with an irreversible combination event for apo(a) and apoB-100 in Lp(a). Indeed, the authors offered a model in which apo(a) recycles on and off VLDL [forming a TG-rich Lp(a) at least once before leaving plasma] (48.Diffenderfer M.R. Lamon-Fava S. Marcovina S.M. Barrett P.H. Lel J. Dolnikowski G.G. Berglund L. Schaefer E.J. Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a).Metabolism. 2016; 65: 381-390Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Of note, the subjects studied by Jenner et al. (47.Jenner J.L. Seman L.J. Millar J.S. Lamon-Fava S. Welty F.K. Dolnikowski G.G. Marcovina S.M. Lichtenstein A.H. Barrett P.H. deLuca C. et al.The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings.Metabolism. 2005; 54: 361-369Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) had baseline lipid levels similar to subjects in other studies in which FCRs for Lp(a)-apo(a) and Lp(a)-apoB-100 were the same (32.Su W. Campos H. Judge H. Walsh B.W. Sacks F.M. Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement.J. Clin. Endocrinol. Metab. 1998; 83: 3267-3276Crossref PubMed Scopus (65) Google Scholar, 33.Frischmann M.E. Ikewaki K. Trenkwalder E. Lamina C. Dieplinger B. Soufi M. Schweer H. Schaefer J.R. Konig P. Kronenberg F. et al.In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a).Atherosclerosis. 2012; 225: 322-327Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 35.Chiesa G. Hobbs H.H. Koschinsky M.L. Lawn R.M. Maika S.D. Hammer R.E. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a).J. Biol. Chem. 1992; 267: 24369-24374Abstract Full Text PDF PubMed Google Scholar), whereas the four subjects studied by Diffenderfer et al. (48.Diffenderfer M.R. Lamon-Fava S. Marcovina S.M. Barrett P.H. Lel J. Dolnikowski G.G. Berglund L. Schaefer E.J. Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a).Metabolism. 2016; 65: 381-390Abstract Full Tex

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