REVIEW URRENT C OPINION
Lipoprotein(a) metabolism Stefania Lamon-Fava a,b, Margaret R. Diffenderfer a, and Santica M. Marcovina c
Purpose of review Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein. The metabolism of this lipoprotein is still not well understood. Recent findings It has long been known that the plasma concentration of Lp(a) is highly heritable, with its genetic determinants located in the apo(a) locus and regulating the rate of hepatic apo(a) production. Recent human intervention trials have convincingly established that, in addition to apo(a) production, hepatic apoB100 production plays an important role in Lp(a) levels. Although the major site and mode of Lp(a) clearance remain unidentified, a recent cell and animal study points to the involvement of the hepatic scavenger receptor class B type I in the uptake of both the lipid and protein constituents of Lp(a) from plasma. Summary Progress in the understanding of Lp(a) metabolism has the potential to lead to the development of novel and specific treatments for the reduction of Lp(a) levels and the associated risk of cardiovascular disease. Keywords apo(a), apoB100, kinetics, lipoprotein(a), metabolism
INTRODUCTION Since the discovery of lipoprotein(a) [Lp(a)] in 1963 [1], much work has been done to unveil its metabolism and physiological role in coronary heart disease (CHD). However, much is still unknown about this lipoprotein. Lp(a) is commonly described as an LDL-like lipoprotein particle with one molecule of apo(a), a large hydrophilic glycoprotein, covalently bound to apoB100 by a disulfide bond [2,3]. The gene coding for apo(a) sits on chromosome 6 in close proximity with the plasminogen gene [4]. The high degree of homology between specific domains of these two proteins and the presence of Lp(a) primarily in humans and primates are consistent with a gene duplication occurring approximately 33 million years ago [5]. The specific domains of apo(a) that are highly homologous to plasminogen include the protease domain, the kringle 5 domain, and 10 subtypes of the kringle 4 domain, of which the type 2 (kringle 42) is present in multiple copies and is responsible for the high degree of variability in the molecular weight of apo(a). While the majority of Lp(a) particles resemble LDL in density and composition, some Lp(a) particles are akin to VLDL or IDL in lipid content,
and apo(a) immunoreactivity has been reported across the entire density distribution of lipoproteins [6,7]. Plasma levels of Lp(a) vary greatly in the general population, from less than 1 to more than 150 nmol/L, and the distribution in Whites is highly skewed with 50% of individuals having concentrations 22 nmol/L or less [8]. Notably, racial differences exist in Lp(a) concentrations, with Blacks showing higher levels than Whites, Asians, and Hispanics [9 ,10]. Plasma concentrations of Lp(a) are determined in a large part by variations in the apo(a) gene locus, including the number of kringle 42 repeats and specific single nucleotide polymorphisms (SNPs). Individuals carrying small apo(a) &
a
Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, bGerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, USA and cNorthwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington, USA Correspondence to Stefania Lamon-Fava, MD, PhD, Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, 711 Washington Street, Boston, MA 02111. Tel: +1 617 556 3105; e-mail: [email protected] Curr Opin Lipidol 2014, 25:189–193 DOI:10.1097/MOL.0000000000000070
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KEY POINTS Plasma levels of Lp(a) are significant predictors of CHD risk. The production rate of both apo(a) and apoB100 are important determinants of plasma Lp(a) levels. The production rate of apo(a) is mostly controlled by the apo(a) locus, while both genetic and environmental factors affect apoB100 production rate. The catabolism of Lp(a) is still not well understood, but the kidney and the liver may be important sites of Lp(a) clearance via the megalin and scavenger receptor class B type I receptor, respectively.
isoforms have higher Lp(a) levels than individuals expressing large apo(a) isoforms [11]. We [8] and others [12] have shown that the absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk. Two SNPs in the apo(a) gene locus, rs3798220 and rs10455872, are significant predictors of both Lp(a) levels and CHD risk [13]. The association between these gene variants and CHD risk is abolished when plasma Lp(a) levels are entered into the model, supporting the direct association between plasma Lp(a) levels and CHD risk.
LIPOPROTEIN(a) AND CARDIOVASCULAR DISEASE There is strong epidemiological evidence that Lp(a) is an atherogenic lipoprotein. A meta-analysis of 36 prospective studies including 126 634 individuals has clearly demonstrated a significant and independent association between plasma Lp(a) levels and the risk of cardiovascular morbidity and mortality [relative risk for 1 standard deviation (SD) increase in Lp(a): 1.13, confidence interval (CI): 1.09–1.18] [14]. We have also reported a 2.4-fold increase (P < 0.02) in CHD risk after a mean follow-up of 12.3 years in men participating in the Framingham Offspring Study and in the upper tertile of baseline plasma Lp(a) levels, relative to those in the bottom tertile [8]. It was recently reported in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study that treatment with extendedrelease niacin was associated with an overall 21% reduction in Lp(a) levels, but that both baseline and on-treatment levels of Lp(a) were predictors of CHD risk [hazard ratio (HR) for 1 SD increase in Lp(a): 1.16, CI: 1.04–1.28, P < 0.01, and HR: 1.18, CI: 1.00–1.39, P < 0.05, respectively] [15 ]. Similarly, &
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in 7746 White participants in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, a significant increase in CHD risk was documented for each 1 SD increase in baseline Lp(a) levels (HR: 1.18, CI: 1.03–1.34) and on-statin Lp(a) levels (HR: 1.27, CI: 1.01–1.59) [9 ]. By documenting a residual CHD risk associated with high plasma Lp(a) levels in individuals achieving low on-treatment LDL cholesterol levels, these large studies strengthen the concept of the independent and relevant role of Lp(a) in CHD progression. These findings are in contrast with those of a previous smaller study showing reduction in CHD risk associated with high Lp(a) levels in patients who had achieved substantial LDL cholesterol lowering by means of drug treatment [16]. Taken together, these data support an independent and causative role of Lp(a) in cardiovascular disease. There are however no drugs that selectively decrease Lp(a) levels and, hence, little evidence that the selective lowering of Lp(a) would result in a reduction in CHD risk. &
PATHOPHYSIOLOGY OF LIPOPROTEIN(a)ASSOCIATED CORONARY HEART DISEASE Because of the homology between apo(a) and plasminogen, one of the mechanisms that has been proposed for Lp(a) atherogenicity is the inhibition of fibrinolysis. However, a recent large study including 35 case–control series has reported that the two genetic variants determining Lp(a) levels, rs3798220 and rs10455872, were associated with vascular diseases with an atherosclerotic but not a thrombotic component [17]. Lp(a) is commonly found in atherosclerotic plaques, in which Lp(a) participates in the formation of foam cells in a manner similar to LDL. Moreover, Lp(a), via its apo(a) protein and oxidized lipids, promotes multiple oxidative and inflammatory actions on the vascular wall [18,19].
METABOLISM OF LIPOPROTEIN(a) Despite the number of studies examining the kinetics of Lp(a), the exact mode of synthesis and site of catabolism of this lipoprotein is still not well understood. A summary of kinetic studies assessing the kinetics of apo(a) and apoB100 in Lp(a) using stable isotope methodology is provided in Table 1 [20–24]. A similar rate of production and clearance of apo(a) and apoB100 in Lp(a) have been reported in most studies, in which Lp(a) was isolated by ultracentrifugation [20–22,24]. However, a slower clearance of apo(a) than apoB100 was observed in our study [23], in which Lp(a) was isolated from whole plasma by lectin affinity. Volume 25 Number 3 June 2014
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a
d, density; FCR, fractional catabolic rate; imag, immunomagnetic separation with antibody-bound magnetic beads; ippt, immunoprecipitation; i.v., intravenous; ND, no data reported; PCI, primed-constant infusion; WGA, wheat germ agglutinin affinity chromatography. Data are expressed as mean standard deviation (SD). b Fractional synthetic rate, per day. c Production rate is calculated as mg/kg per day1.
1.283 (0.582); 0.832 (0.664) 1.161 (0.696); 1.109 (0.904) 0.299 (0.142); 0.129 (0.097) 0.246 (0.067); 0.164 (0.114) fasting; fasting Nine normolipidemic men; seven hemodialysis men Frischmann et al. [24]
[2H3]-leucine 12 h PCI; [2H3]-leucine; 12 h PCI
d > 1.063 (ultracentrifugation plus imag)
1.53c (0.219) 0.497c (0.078) 0.416 (0.040) 0.220 (0.030) Fed 1/20th of caloric intake hourly 23 normolipidemic (16 men; seven women age >40) Jenner et al [23]
[2H3]-leucine; 15 h PCI
Whole plasma (WGA)
0.146 (0.050)c 0.149 (0.046)c 0.256 (0.083) 0.266 (0.107) Fasting [2H3]-leucine; i.v. bolus or 10 h PCI Seven normolipidemic (five men; two women) Demant et al. [22]
Fed fat-free, leucine-free lunch and dinner (60% of calories) Six postmenopausal women Su et al. [21]
[2H3]-leucine; 12 h PCI
d < 1.15 (WGA plus ultracentrifugation)
0.144 (0.042) 0.155 (0.111) 0.270 (0.155) 0.277 (0.194)
ND 0.139b (0.073) 0.162b (0.084) Not specified (ultracentrifugation and/or ippt) Fed liquid diet hourly (22% fat) [2H4]-lysine; 16 h PCI Five normolipidemic (four men; one woman) Morrisett et al. [20]
Metabolic study Individuals Reference
Tracer
d 1.05–1.15 (ultracentrifugation)
ND
ApoB-100 Apo(a) Apo(a)
ApoB-100
Production rate, nmol/kg per day1 FCR, pools/day
Lp(a) fraction (isolation method]
Table 1. Studies determining the kinetic parameters of apo(a) and apoB100 within Lp(a) by stable isotope and gas chromatography-mass spectrometry methodologya
Li poprotein(a) metabolism Lamon-Fava et al.
Apo(a) and apoB production As indicated above, the production rate of apo(a) is the main determinant of plasma Lp(a) levels [11,23] and, more specifically, the rate of apo(a) production is inversely related to the number of kringle 42 repeats [11]. Other sequences in the apo(a) locus also control plasma Lp(a) levels [13], but it is not known if the regulation occurs transcriptionally or post-transcriptionally. In hepatoma cells, the synthesis and secretion of apo(a) have been coupled with the secretion of triglycerides, suggesting that the apoB100– lipid assembly is also a determinant of Lp(a) production [25]. Recent randomized clinical trials of new therapeutic agents have also provided clear evidence of the important role of hepatic apoB100 synthesis and secretion on plasma Lp(a) levels. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP), a protein required for the assembly of apoB-containing lipoproteins in the endoplasmic reticulum. In a single-arm, open-label clinical trial [26] conducted in 29 patients with homozygous familial hypercholesterolemia, lomitapide significantly reduced plasma Lp(a) levels by 15% and total apoB levels by 49% over a period of 26 weeks. These findings are in agreement with the observation of low plasma Lp(a) concentrations in individuals with abetalipoproteinemia because of a loss-of-function mutation in the MTP gene [27]. Another experimental drug designed to lower plasma LDL cholesterol levels, mipomersen, is a small oligonucleotide binding to apoB mRNA and thus preventing apoB translation and secretion. In a randomized, double-blind, placebo-controlled study of 45 homozygous familial hypercholesterolemia patients [28], mipomersen significantly reduced plasma Lp(a) levels by 31% and total apoB levels by 27% over a period of 26 weeks. In another study conducted in both homozygous and heterozygous familial hypercholesterolemia (n ¼ 53) [29], the Lp(a) lowering effects of mipomersen were sustained over a period of 2 years [Lp(a): 14%; apoB: 31%]. Hepatic apoB synthesis and secretion are modulated also by proprotein convertase subtilisin/kexin type 9 (PCSK9) independently of the LDL receptor: overexpression of PCSK9 in mice has been shown to increase hepatic apoB synthesis possibly via an intracellular PCSK9/ apoB protein interaction and subsequent inhibition of apoB degradation [30]. In support of these findings, AMG-145, a monoclonal antibody against PCSK9, significantly reduced plasma Lp(a) levels by up to 32% at the maximal dose of 140 mg/2 weeks over a period of 12 weeks in a randomized, placebocontrolled study of 626 individuals with hypercholesterolemia [31]. Taken together, human kinetics data and recent clinical trials of apoB lowering drugs support the concept that both apo(a) synthesis and
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apoB synthesis are important regulators of Lp(a) particle assembly and secretion. One of the relevant questions pertaining to the production of Lp(a) is the site of apo(a)–apoB100 assembly. The literature is divided on this, with some work [25] performed in isolated hepatocytes or HepG2 cells supporting intracellular assembly and others [32,33] demonstrating extracellular association. Recently, Frischmann et al. [34] studied the in-vivo kinetics of apo(a) and apoB100 in Lp(a) in nine healthy men in the fasting state using a multicompartmental model and reported that 92% of circulating Lp(a) originated from intracellular assembly of apo(a) and apoB100 and only 8% by extracellular association of apo(a) with LDL. This is in contrast with our study in 23 individuals in the fed state, in whom the clearance of apo(a) and apoB-100 within plasma Lp(a) were significantly different (mean SEM, 0.220 0.030 and 0.416 0.040 pools/day, respectively; P < 0.001) [23]. In this study, Lp(a) was isolated from whole plasma using a lectin affinity-based method. Our findings suggested different metabolic fates for apo(a) and apoB-100 within Lp(a) in the fed state and lead us to hypothesize that apo(a) does not remain covalently linked to a single apoB100 lipoprotein but that it reassociates at least once with another apoB-100 particle during its plasma residence [23]. Similarly, Demant et al. [22] have studied the kinetics of Lp(a) isolated from whole plasma using lectin affinity and a multicompartmental model in seven healthy normocholesterolemic individuals and found that apoB100 in Lp(a) originated from two different sources: 53% originated from de novo hepatic synthesis and the remaining from plasma LDL or intermediate density lipoprotein (IDL). Both our study and Demant et al.’s [22] study are consistent with a model requiring a fraction of plasma Lp(a) be derived from extracellular assembly of apo(a) and apoB100.
Lipoprotein(a) catabolism Little is known about the mode and site of Lp(a) catabolism. While Lp(a) comprises an LDL-like particle, it appears that apoB in Lp(a) does not readily interact with the LDL receptor, and thus this receptor does not play a role in Lp(a) kinetics [35]. The elevated Lp(a) levels observed in individuals with familial hypercholesterolemia may be linked to the increased LDL apoB100 production in these individuals, rather than reduced clearance. However, Lp(a) has been shown to bind to megalin/glycoprotein 330, a receptor member of the LDL receptor family and highly expressed in kidneys [36]. Of interest, patients with advanced chronic kidney disease have elevated plasma levels of Lp(a) compared to healthy individuals [37]. To investigate the contribution of the 192
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kidney to Lp(a) catabolism, Frischmann et al. [24] have conducted a stable isotope kinetic study in seven hemodialysis patients and nine healthy controls. The study showed a significantly lower fractional catabolic rate of apo(a) and apoB in Lp(a) in hemodialysis patients, but similar production rate, relative to healthy controls, supporting a significant role of the kidney in the clearance of plasma Lp(a) [24,38]. Recently, the scavenger receptor class B type I (SR-BI) was identified as a receptor involved in Lp(a) catabolism. SR-BI is expressed in liver, macrophages, and steroidogenic tissues, in addition to several other tissues, and is known to bind HDL and LDL, playing a role both in reverse cholesterol transport and atherogenesis. Using cells overexpressing or not expressing SR-BI, both the lipid and protein components of Lp(a) were shown to be cleared by this cell membrane receptor [39 ]. The role of SR-BI in Lp(a) catabolism was confirmed in wild-type, SR-BI knockout, and liver-specific SR-BI transgenic mice. The data indicated that the clearance of Lp(a)-lipids was three-fold higher in SR-BI transgenic mice than control mice but delayed in SR-BI knockout mice, pointing to a significant role of this receptor in Lp(a) catabolism [39 ]. The observation that 65% of injected labeled Lp(a) was removed in SR-BI knockout mice after 24 h suggested, however, that the SR-BI may not be the main pathway of Lp(a) clearance [39 ]. &&
&&
&&
CONCLUSION The metabolism of Lp(a) is complex and not well understood. Plasma levels of Lp(a) are for the most part genetically determined and dependent on the rate of hepatic apo(a) and apoB100 synthesis and secretion. Once secreted, Lp(a) may undergo dissociation of its apo(a) constituent which will reassemble with another circulating apoB100-containng lipoprotein before clearance by the megalin, the SR-BI, or possibly other receptors. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Berg K. A new serum type system in man – the Lp system. Acta pathol Microbiol Scand 1963; 59:369–382.
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Li poprotein(a) metabolism Lamon-Fava et al. 2. Utermann G, Weber W. Protein composition of Lp(a) lipoprotein from human plasma. FEBS Lett 1983; 154:357–361. 3. Gaubatz JW, Heideman C, Gotto AM Jr, et al. Human plasma lipoprotein [a]. Structural properties. J Biol Chem 1983; 258:4582–4589. 4. Frank SL, Klisak I, Sparkes RS, et al. The apolipoprotein(a) gene resides on human chromosome 6q26-27, in close proximity to the homologous gene for plasminogen. Hum Genet 1988; 79:352–356. 5. Lawn RM, Schwartz K, Patthy L. Convergent evolution of apolipoprotein(a) in primates and hedgehog. Proc Natl Acad Sci U S A 1997; 94:11992–11997. 6. Seman LJ, Breckenridge WC. Isolation and partial characterization of apolipoprotein (a) from human lipoprotein (a). Biochem Cell Biol 1986; 64:999– 1009. 7. Klezovitch O, Scanu AM. Heterogeneity of lipoprotein (a): growing complexities. Curr Opin Lipidol 1995; 6:223–228. 8. Lamon-Fava S, Marcovina SM, Albers JJ, et al. Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study. J Lipid Res 2011; 52:1181–1187. 9. Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, & rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial. Circulation 2013. This large randomized clinical trial demostrates that plasma Lp(a) is a significant determinant of CHD risk in individuals treated with statins. 10. Marcovina SM, Albers JJ, Wijsman E, et al. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res 1996; 37:2569–2585. 11. 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 differences in production rate. J Clin Invest 1994; 93:2758–2763. 12. Hopewell JC, Seedorf U, Farrall M, et al. Impact of lipoprotein(a) levels and apolipoprotein(a) isoform size on risk of coronary heart disease. J Intern Med 2013. 13. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361:2518–2528. 14. Erqou S, Kaptoge S, et al., Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302:412–423. 15. Albers JJ, Slee A, O’Brien KD, et al. Relationship of apolipoproteins A-1 and B, & and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013; 62:1575–1579. This study demonstrates the significant and independent contribution of plasma Lp(a) to residual CHD risk in individuals who have achieved low LDL cholesterol levels by means of pharmacological treatment. 16. Maher VM, Brown BG, Marcovina SM, et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995; 274: 1771–1774. 17. Helgadottir A, Gretarsdottir S, Thorleifsson G, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol 2012; 60:722–729. 18. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol 2012; 60:716–721. 19. Sotiriou SN, Orlova VV, Al-Fakhri N, et al. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J 2006; 20:559–561. 20. Morrisett JD, Gaubatz JW, Nava MN, et al. Metabolism of apo(a) and apo-B100 in human lipoprotein(a). Med Sci Symp Ser 1993; 2:161–167.
21. Su W, Campos H, Judge H, et al. Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement. J Clin Endocrinol Metab 1998; 83:3267–3276. 22. 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; 157:325–339. 23. Jenner JL, Seman LJ, Millar JS, et al. The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings. Metabolism 2005; 54:361–369. 24. Frischmann ME, Kronenberg F, Trenkwalder E, et al. In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int 2007; 71:1036–1043. 25. Nassir F, Bonen DK, Davidson NO. Apolipoprotein(a) synthesis and secretion from hepatoma cells is coupled to triglyceride synthesis and secretion. J Biol Chem 1998; 273:17793–17800. 26. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40–46. 27. Menzel HJ, Dieplinger H, Lackner C, et al. Abetalipoproteinemia with an ApoB100-lipoprotein(a) glycoprotein complex in plasma. Indication for an assembly defect. J Biol Chem 1990; 265:981–986. 28. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375:998–1006. 29. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2013. 30. Sun H, Samarghandi A, Zhang N, et al. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol 2012; 32:1585–1595. 31. Desai NR, Giugliano RP, Zhou J, et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of NCEP-ATP III LDL-C goals among high risk patients: an analysis from the LAPLACE-TIMI 57 trial. J Am Coll Cardiol 2014; 63:430–433. 32. White AL, Rainwater DL, Hixson JE, et al. Intracellular processing of apo(a) in primary baboon hepatocytes. Chem Phys Lipids 1994; 67–68:123– 133. 33. Lobentanz EM, Krasznai K, Gruber A, et al. Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells. Biochemistry 1998; 37:5417–5425. 34. Frischmann ME, Ikewaki K, Trenkwalder E, et al. In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a). Atherosclerosis 2012; 225:322–327. 35. Rader DJ, Mann WA, Cain W, et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest 1995; 95:1403–1408. 36. Niemeier A, Willnow T, Dieplinger H, et al. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro. Arterioscler Thromb Vasc Biol 1999; 19:552–561. 37. Kronenberg F, Utermann G, Dieplinger H. Lipoprotein(a) in renal disease. Am J Kidney Dis 1996; 27:1–25. 38. Ikewaki K. In vivo kinetic studies to further understand pathogenesis of abnormal lipoprotein metabolism in chronic kidney disease. Clin Exp Nephrol 2013. 39. Yang XP, Amar MJ, Vaisman B, et al. Scavenger receptor-BI is a receptor for && lipoprotein(a). J Lipid Res 2013; 54:2450–2457. This study demostrates that the hepatic scavenger receptor class B type Iparticipates in whole particle, and possibly selected lipid, uptake of Lp(a).
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Lipoprotein(a) metabolism Stefania Lamon-Fava a,b, Margaret R. Diffenderfer a, and Santica M. Marcovina c
Purpose of review Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein. The metabolism of this lipoprotein is still not well understood. Recent findings It has long been known that the plasma concentration of Lp(a) is highly heritable, with its genetic determinants located in the apo(a) locus and regulating the rate of hepatic apo(a) production. Recent human intervention trials have convincingly established that, in addition to apo(a) production, hepatic apoB100 production plays an important role in Lp(a) levels. Although the major site and mode of Lp(a) clearance remain unidentified, a recent cell and animal study points to the involvement of the hepatic scavenger receptor class B type I in the uptake of both the lipid and protein constituents of Lp(a) from plasma. Summary Progress in the understanding of Lp(a) metabolism has the potential to lead to the development of novel and specific treatments for the reduction of Lp(a) levels and the associated risk of cardiovascular disease. Keywords apo(a), apoB100, kinetics, lipoprotein(a), metabolism
INTRODUCTION Since the discovery of lipoprotein(a) [Lp(a)] in 1963 [1], much work has been done to unveil its metabolism and physiological role in coronary heart disease (CHD). However, much is still unknown about this lipoprotein. Lp(a) is commonly described as an LDL-like lipoprotein particle with one molecule of apo(a), a large hydrophilic glycoprotein, covalently bound to apoB100 by a disulfide bond [2,3]. The gene coding for apo(a) sits on chromosome 6 in close proximity with the plasminogen gene [4]. The high degree of homology between specific domains of these two proteins and the presence of Lp(a) primarily in humans and primates are consistent with a gene duplication occurring approximately 33 million years ago [5]. The specific domains of apo(a) that are highly homologous to plasminogen include the protease domain, the kringle 5 domain, and 10 subtypes of the kringle 4 domain, of which the type 2 (kringle 42) is present in multiple copies and is responsible for the high degree of variability in the molecular weight of apo(a). While the majority of Lp(a) particles resemble LDL in density and composition, some Lp(a) particles are akin to VLDL or IDL in lipid content,
and apo(a) immunoreactivity has been reported across the entire density distribution of lipoproteins [6,7]. Plasma levels of Lp(a) vary greatly in the general population, from less than 1 to more than 150 nmol/L, and the distribution in Whites is highly skewed with 50% of individuals having concentrations 22 nmol/L or less [8]. Notably, racial differences exist in Lp(a) concentrations, with Blacks showing higher levels than Whites, Asians, and Hispanics [9 ,10]. Plasma concentrations of Lp(a) are determined in a large part by variations in the apo(a) gene locus, including the number of kringle 42 repeats and specific single nucleotide polymorphisms (SNPs). Individuals carrying small apo(a) &
a
Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, bGerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, USA and cNorthwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington, USA Correspondence to Stefania Lamon-Fava, MD, PhD, Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, 711 Washington Street, Boston, MA 02111. Tel: +1 617 556 3105; e-mail: [email protected] Curr Opin Lipidol 2014, 25:189–193 DOI:10.1097/MOL.0000000000000070
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Lipid metabolism
KEY POINTS Plasma levels of Lp(a) are significant predictors of CHD risk. The production rate of both apo(a) and apoB100 are important determinants of plasma Lp(a) levels. The production rate of apo(a) is mostly controlled by the apo(a) locus, while both genetic and environmental factors affect apoB100 production rate. The catabolism of Lp(a) is still not well understood, but the kidney and the liver may be important sites of Lp(a) clearance via the megalin and scavenger receptor class B type I receptor, respectively.
isoforms have higher Lp(a) levels than individuals expressing large apo(a) isoforms [11]. We [8] and others [12] have shown that the absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk. Two SNPs in the apo(a) gene locus, rs3798220 and rs10455872, are significant predictors of both Lp(a) levels and CHD risk [13]. The association between these gene variants and CHD risk is abolished when plasma Lp(a) levels are entered into the model, supporting the direct association between plasma Lp(a) levels and CHD risk.
LIPOPROTEIN(a) AND CARDIOVASCULAR DISEASE There is strong epidemiological evidence that Lp(a) is an atherogenic lipoprotein. A meta-analysis of 36 prospective studies including 126 634 individuals has clearly demonstrated a significant and independent association between plasma Lp(a) levels and the risk of cardiovascular morbidity and mortality [relative risk for 1 standard deviation (SD) increase in Lp(a): 1.13, confidence interval (CI): 1.09–1.18] [14]. We have also reported a 2.4-fold increase (P < 0.02) in CHD risk after a mean follow-up of 12.3 years in men participating in the Framingham Offspring Study and in the upper tertile of baseline plasma Lp(a) levels, relative to those in the bottom tertile [8]. It was recently reported in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study that treatment with extendedrelease niacin was associated with an overall 21% reduction in Lp(a) levels, but that both baseline and on-treatment levels of Lp(a) were predictors of CHD risk [hazard ratio (HR) for 1 SD increase in Lp(a): 1.16, CI: 1.04–1.28, P < 0.01, and HR: 1.18, CI: 1.00–1.39, P < 0.05, respectively] [15 ]. Similarly, &
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in 7746 White participants in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, a significant increase in CHD risk was documented for each 1 SD increase in baseline Lp(a) levels (HR: 1.18, CI: 1.03–1.34) and on-statin Lp(a) levels (HR: 1.27, CI: 1.01–1.59) [9 ]. By documenting a residual CHD risk associated with high plasma Lp(a) levels in individuals achieving low on-treatment LDL cholesterol levels, these large studies strengthen the concept of the independent and relevant role of Lp(a) in CHD progression. These findings are in contrast with those of a previous smaller study showing reduction in CHD risk associated with high Lp(a) levels in patients who had achieved substantial LDL cholesterol lowering by means of drug treatment [16]. Taken together, these data support an independent and causative role of Lp(a) in cardiovascular disease. There are however no drugs that selectively decrease Lp(a) levels and, hence, little evidence that the selective lowering of Lp(a) would result in a reduction in CHD risk. &
PATHOPHYSIOLOGY OF LIPOPROTEIN(a)ASSOCIATED CORONARY HEART DISEASE Because of the homology between apo(a) and plasminogen, one of the mechanisms that has been proposed for Lp(a) atherogenicity is the inhibition of fibrinolysis. However, a recent large study including 35 case–control series has reported that the two genetic variants determining Lp(a) levels, rs3798220 and rs10455872, were associated with vascular diseases with an atherosclerotic but not a thrombotic component [17]. Lp(a) is commonly found in atherosclerotic plaques, in which Lp(a) participates in the formation of foam cells in a manner similar to LDL. Moreover, Lp(a), via its apo(a) protein and oxidized lipids, promotes multiple oxidative and inflammatory actions on the vascular wall [18,19].
METABOLISM OF LIPOPROTEIN(a) Despite the number of studies examining the kinetics of Lp(a), the exact mode of synthesis and site of catabolism of this lipoprotein is still not well understood. A summary of kinetic studies assessing the kinetics of apo(a) and apoB100 in Lp(a) using stable isotope methodology is provided in Table 1 [20–24]. A similar rate of production and clearance of apo(a) and apoB100 in Lp(a) have been reported in most studies, in which Lp(a) was isolated by ultracentrifugation [20–22,24]. However, a slower clearance of apo(a) than apoB100 was observed in our study [23], in which Lp(a) was isolated from whole plasma by lectin affinity. Volume 25 Number 3 June 2014
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a
d, density; FCR, fractional catabolic rate; imag, immunomagnetic separation with antibody-bound magnetic beads; ippt, immunoprecipitation; i.v., intravenous; ND, no data reported; PCI, primed-constant infusion; WGA, wheat germ agglutinin affinity chromatography. Data are expressed as mean standard deviation (SD). b Fractional synthetic rate, per day. c Production rate is calculated as mg/kg per day1.
1.283 (0.582); 0.832 (0.664) 1.161 (0.696); 1.109 (0.904) 0.299 (0.142); 0.129 (0.097) 0.246 (0.067); 0.164 (0.114) fasting; fasting Nine normolipidemic men; seven hemodialysis men Frischmann et al. [24]
[2H3]-leucine 12 h PCI; [2H3]-leucine; 12 h PCI
d > 1.063 (ultracentrifugation plus imag)
1.53c (0.219) 0.497c (0.078) 0.416 (0.040) 0.220 (0.030) Fed 1/20th of caloric intake hourly 23 normolipidemic (16 men; seven women age >40) Jenner et al [23]
[2H3]-leucine; 15 h PCI
Whole plasma (WGA)
0.146 (0.050)c 0.149 (0.046)c 0.256 (0.083) 0.266 (0.107) Fasting [2H3]-leucine; i.v. bolus or 10 h PCI Seven normolipidemic (five men; two women) Demant et al. [22]
Fed fat-free, leucine-free lunch and dinner (60% of calories) Six postmenopausal women Su et al. [21]
[2H3]-leucine; 12 h PCI
d < 1.15 (WGA plus ultracentrifugation)
0.144 (0.042) 0.155 (0.111) 0.270 (0.155) 0.277 (0.194)
ND 0.139b (0.073) 0.162b (0.084) Not specified (ultracentrifugation and/or ippt) Fed liquid diet hourly (22% fat) [2H4]-lysine; 16 h PCI Five normolipidemic (four men; one woman) Morrisett et al. [20]
Metabolic study Individuals Reference
Tracer
d 1.05–1.15 (ultracentrifugation)
ND
ApoB-100 Apo(a) Apo(a)
ApoB-100
Production rate, nmol/kg per day1 FCR, pools/day
Lp(a) fraction (isolation method]
Table 1. Studies determining the kinetic parameters of apo(a) and apoB100 within Lp(a) by stable isotope and gas chromatography-mass spectrometry methodologya
Li poprotein(a) metabolism Lamon-Fava et al.
Apo(a) and apoB production As indicated above, the production rate of apo(a) is the main determinant of plasma Lp(a) levels [11,23] and, more specifically, the rate of apo(a) production is inversely related to the number of kringle 42 repeats [11]. Other sequences in the apo(a) locus also control plasma Lp(a) levels [13], but it is not known if the regulation occurs transcriptionally or post-transcriptionally. In hepatoma cells, the synthesis and secretion of apo(a) have been coupled with the secretion of triglycerides, suggesting that the apoB100– lipid assembly is also a determinant of Lp(a) production [25]. Recent randomized clinical trials of new therapeutic agents have also provided clear evidence of the important role of hepatic apoB100 synthesis and secretion on plasma Lp(a) levels. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP), a protein required for the assembly of apoB-containing lipoproteins in the endoplasmic reticulum. In a single-arm, open-label clinical trial [26] conducted in 29 patients with homozygous familial hypercholesterolemia, lomitapide significantly reduced plasma Lp(a) levels by 15% and total apoB levels by 49% over a period of 26 weeks. These findings are in agreement with the observation of low plasma Lp(a) concentrations in individuals with abetalipoproteinemia because of a loss-of-function mutation in the MTP gene [27]. Another experimental drug designed to lower plasma LDL cholesterol levels, mipomersen, is a small oligonucleotide binding to apoB mRNA and thus preventing apoB translation and secretion. In a randomized, double-blind, placebo-controlled study of 45 homozygous familial hypercholesterolemia patients [28], mipomersen significantly reduced plasma Lp(a) levels by 31% and total apoB levels by 27% over a period of 26 weeks. In another study conducted in both homozygous and heterozygous familial hypercholesterolemia (n ¼ 53) [29], the Lp(a) lowering effects of mipomersen were sustained over a period of 2 years [Lp(a): 14%; apoB: 31%]. Hepatic apoB synthesis and secretion are modulated also by proprotein convertase subtilisin/kexin type 9 (PCSK9) independently of the LDL receptor: overexpression of PCSK9 in mice has been shown to increase hepatic apoB synthesis possibly via an intracellular PCSK9/ apoB protein interaction and subsequent inhibition of apoB degradation [30]. In support of these findings, AMG-145, a monoclonal antibody against PCSK9, significantly reduced plasma Lp(a) levels by up to 32% at the maximal dose of 140 mg/2 weeks over a period of 12 weeks in a randomized, placebocontrolled study of 626 individuals with hypercholesterolemia [31]. Taken together, human kinetics data and recent clinical trials of apoB lowering drugs support the concept that both apo(a) synthesis and
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Lipid metabolism
apoB synthesis are important regulators of Lp(a) particle assembly and secretion. One of the relevant questions pertaining to the production of Lp(a) is the site of apo(a)–apoB100 assembly. The literature is divided on this, with some work [25] performed in isolated hepatocytes or HepG2 cells supporting intracellular assembly and others [32,33] demonstrating extracellular association. Recently, Frischmann et al. [34] studied the in-vivo kinetics of apo(a) and apoB100 in Lp(a) in nine healthy men in the fasting state using a multicompartmental model and reported that 92% of circulating Lp(a) originated from intracellular assembly of apo(a) and apoB100 and only 8% by extracellular association of apo(a) with LDL. This is in contrast with our study in 23 individuals in the fed state, in whom the clearance of apo(a) and apoB-100 within plasma Lp(a) were significantly different (mean SEM, 0.220 0.030 and 0.416 0.040 pools/day, respectively; P < 0.001) [23]. In this study, Lp(a) was isolated from whole plasma using a lectin affinity-based method. Our findings suggested different metabolic fates for apo(a) and apoB-100 within Lp(a) in the fed state and lead us to hypothesize that apo(a) does not remain covalently linked to a single apoB100 lipoprotein but that it reassociates at least once with another apoB-100 particle during its plasma residence [23]. Similarly, Demant et al. [22] have studied the kinetics of Lp(a) isolated from whole plasma using lectin affinity and a multicompartmental model in seven healthy normocholesterolemic individuals and found that apoB100 in Lp(a) originated from two different sources: 53% originated from de novo hepatic synthesis and the remaining from plasma LDL or intermediate density lipoprotein (IDL). Both our study and Demant et al.’s [22] study are consistent with a model requiring a fraction of plasma Lp(a) be derived from extracellular assembly of apo(a) and apoB100.
Lipoprotein(a) catabolism Little is known about the mode and site of Lp(a) catabolism. While Lp(a) comprises an LDL-like particle, it appears that apoB in Lp(a) does not readily interact with the LDL receptor, and thus this receptor does not play a role in Lp(a) kinetics [35]. The elevated Lp(a) levels observed in individuals with familial hypercholesterolemia may be linked to the increased LDL apoB100 production in these individuals, rather than reduced clearance. However, Lp(a) has been shown to bind to megalin/glycoprotein 330, a receptor member of the LDL receptor family and highly expressed in kidneys [36]. Of interest, patients with advanced chronic kidney disease have elevated plasma levels of Lp(a) compared to healthy individuals [37]. To investigate the contribution of the 192
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kidney to Lp(a) catabolism, Frischmann et al. [24] have conducted a stable isotope kinetic study in seven hemodialysis patients and nine healthy controls. The study showed a significantly lower fractional catabolic rate of apo(a) and apoB in Lp(a) in hemodialysis patients, but similar production rate, relative to healthy controls, supporting a significant role of the kidney in the clearance of plasma Lp(a) [24,38]. Recently, the scavenger receptor class B type I (SR-BI) was identified as a receptor involved in Lp(a) catabolism. SR-BI is expressed in liver, macrophages, and steroidogenic tissues, in addition to several other tissues, and is known to bind HDL and LDL, playing a role both in reverse cholesterol transport and atherogenesis. Using cells overexpressing or not expressing SR-BI, both the lipid and protein components of Lp(a) were shown to be cleared by this cell membrane receptor [39 ]. The role of SR-BI in Lp(a) catabolism was confirmed in wild-type, SR-BI knockout, and liver-specific SR-BI transgenic mice. The data indicated that the clearance of Lp(a)-lipids was three-fold higher in SR-BI transgenic mice than control mice but delayed in SR-BI knockout mice, pointing to a significant role of this receptor in Lp(a) catabolism [39 ]. The observation that 65% of injected labeled Lp(a) was removed in SR-BI knockout mice after 24 h suggested, however, that the SR-BI may not be the main pathway of Lp(a) clearance [39 ]. &&
&&
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CONCLUSION The metabolism of Lp(a) is complex and not well understood. Plasma levels of Lp(a) are for the most part genetically determined and dependent on the rate of hepatic apo(a) and apoB100 synthesis and secretion. Once secreted, Lp(a) may undergo dissociation of its apo(a) constituent which will reassemble with another circulating apoB100-containng lipoprotein before clearance by the megalin, the SR-BI, or possibly other receptors. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Berg K. A new serum type system in man – the Lp system. Acta pathol Microbiol Scand 1963; 59:369–382.
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