Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 10, 2022

Hypertriglyceridemia, a causal risk factor for atherosclerosis, and its laboratory assessment

  • Ewa Wieczorek ORCID logo EMAIL logo , Agnieszka Ćwiklińska and Maciej Jankowski

Abstract

Epidemiological and clinical studies show a causal association between serum triglyceride (TG) level, the number of triglyceride-rich lipoproteins (TRLs) and their remnants, and the increased risk of atherosclerosis and cardiovascular disease (CVD) development. In light of current guidelines for dyslipidemia management, the laboratory parameters reflecting TRL content are recommended as part of the routine lipid analysis process and used for CVD risk assessment, especially in people with hypertriglyceridemia (HTG), diabetes mellitus, obesity and low levels of low-density lipoprotein cholesterol (LDL-C), in which high residual CVD risk is observed. The basic routinely available laboratory parameters related with TRL are serum TG and non-high-density lipoprotein cholesterol (non-HDL-C) levels, but there are also other biomarkers related to TRL metabolism, the determination of which can be helpful in identifying the basis of HTG development or assessing CVD risk or can be the target of pharmacological intervention. In this review, we present the currently available laboratory parameters related to HTG. We summarise their link with TRL metabolism and HTG development, the determination methods as well as their clinical significance, the target values and interpretation of the results in relation to the current dyslipidemia guidelines.


Corresponding author: Ewa Wieczorek, MSc, Department of Clinical Chemistry, Medical University of Gdańsk, Dębinki 7 Street, 80-211 Gdańsk, Poland, Phone: +48 583492777, E-mail:

Acknowledgments

Not applicable.

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Tóth, PP, Potter, D, Ming, EE. Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003-2006. J Clin Lipidol 2012;6:325–30.10.1016/j.jacl.2012.05.002Search in Google Scholar

2. Parhofer, KG, Laufs, U. The diagnosis and treatment of hypertriglyceridemia. Dtsch Arztebl Int 2019;116:825–32. https://doi.org/10.3238/arztebl.2019.0825.Search in Google Scholar

3. Nordestgaard, BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63. https://doi.org/10.1161/circresaha.115.306249.Search in Google Scholar

4. Nordestgaard, BG, Varbo, A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35. https://doi.org/10.1016/s0140-6736(14)61177-6.Search in Google Scholar

5. Meldrum, DR, Morris, MA, Gambone, JC. Obesity pandemic: causes, consequences, and solutions—but do we have the will? Fertil Steril 2017;107:833–9. https://doi.org/10.1016/j.fertnstert.2017.02.104.Search in Google Scholar

6. Ginsberg, HN, Packard, CJ, Chapman, MJ, Borén, J, Aguilar-Salinas, CA, Averna, M, et al.. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791–806. https://doi.org/10.1093/eurheartj/ehab551.Search in Google Scholar

7. Mach, F, Baignet, C, Catapano, AL, Koskinas, KC, Casula, M, Badimon, L, et al.. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88. https://doi.org/10.1093/eurheartj/ehz455.Search in Google Scholar

8. Jørgensen, AB, Frikke-Schmidt, R, Nordestgaard, BG, Tybjærg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32–41.10.1056/NEJMoa1308027Search in Google Scholar

9. Sarwar, N, Sandhu, MS, Ricketts, SL, Butterworth, AS, Di Angelantonio, E, Boekholdt, SM, et al.. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010;375:1634–9. https://doi.org/10.1016/S0140-6736(10)60545-4.Search in Google Scholar

10. Varbo, A, Nordestgaard, BG, Tybjrg-Hansen, A, Schnohr, P, Jensen, GB, Benn, M. Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population. Ann Neurol 2011;69:628–34. https://doi.org/10.1002/ana.22384.Search in Google Scholar PubMed

11. Nordestgaard, BG, Benn, M, Schnohr, P, Tybjærg-Hansen, A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308. https://doi.org/10.1001/jama.298.3.299.Search in Google Scholar

12. Jun, M, Foote, C, Lv, J, Neal, B, Patel, A, Nicholls, SJ, et al.. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875–84. https://doi.org/10.1016/s0140-6736(10)60656-3.Search in Google Scholar

13. Laufs, U, Parhofer, KG, Ginsberg, HN, Hegele, RA. Clinical review on triglycerides. Eur Heart J 2020;41:99–109. https://doi.org/10.1093/eurheartj/ehz785.Search in Google Scholar PubMed PubMed Central

14. Solnica, B, Sygitowicz, G, Sitkiewicz, D, Cybulska, B, Jóźwiak, J, Odrowąż-Sypniewska, G, et al.. 2020 Guidelines of the polish society of laboratory diagnostics (PSLD) and the polish lipid association (PoLA) on laboratory diagnostics of lipid metabolism disorders. Arch Med Sci 2020;16:237–52. https://doi.org/10.5114/aoms.2020.93253.Search in Google Scholar PubMed PubMed Central

15. Emerging Risk Factors Collaboration, Di Angelantonio, E, Gao, P, Pennells, L, Kaptoge, S, Caslake, M, et al.. Lipid-related markers and cardiovascular disease prediction. JAMA 2012;307:2499–506. https://doi.org/10.1001/jama.2012.6571.Search in Google Scholar PubMed PubMed Central

16. Dominiczak, MH, Caslake, MJ. Apolipoproteins: metabolic role and clinical biochemistry applications. Ann Clin Biochem 2011;48:498–515. https://doi.org/10.1258/acb.2011.011111.Search in Google Scholar PubMed

17. Ooi, EMM, Barrett, PHR, Chan, DC, Watts, GF. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond) 2008;114:611–24. https://doi.org/10.1042/cs20070308.Search in Google Scholar PubMed

18. Kei, AA, Filippatos, TD, Tsimihodimos, V, Elisaf, MS. A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease. Metabolism 2012;61:906–21. https://doi.org/10.1016/j.metabol.2011.12.002.Search in Google Scholar PubMed

19. Peng, J, Luo, F, Ruan, G, Peng, R, Li, X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis 2017;16:1–12. https://doi.org/10.1186/s12944-017-0625-0.Search in Google Scholar PubMed PubMed Central

20. Björnson, E, Adiels, M, Taskinen, M-R, Borén, J. Kinetics of plasma triglycerides in abdominal obesity. Curr Opin Lipidol 2017;28:11–8.10.1097/MOL.0000000000000375Search in Google Scholar PubMed

21. Borén, J, Watts, GF, Adiels, M, Söderlund, S, Chan, DC, Hakkarainen, A, et al.. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol 2015;35:2218–24.10.1161/ATVBAHA.115.305614Search in Google Scholar PubMed

22. Ćwiklińska, A, Wieczorek, E, Gliwińska, A, Marcinkowska, M, Czaplińska, M, Mickiewicz, A, et al.. Non-HDL-C/TG ratio indicates significant underestimation of calculated low-density lipoprotein cholesterol (LDL-C) better than TG level: a study on the reliability of mathematical formulas used for LDL-C estimation. Clin Chem Lab Med 2020;59:857–67. https://doi.org/10.1515/cclm-2020-1366.Search in Google Scholar PubMed

23. Nordestgaard, BG, Langsted, A, Mora, S, Kolovou, G, Baum, H, Bruckert, E, et al.. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cutpoints-A joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016;37:1944–58. https://doi.org/10.1093/eurheartj/ehw152.Search in Google Scholar PubMed PubMed Central

24. Langlois, MR, Nordestgaard, BG, Langsted, A, Chapman, MJ, Aakre, KM, Baum, H, et al.. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin Chem Lab Med 2020;58:496–517. https://doi.org/10.1515/cclm-2019-1253.Search in Google Scholar PubMed

25. Ewald, N, Hardt, PD, Kloer, HU. Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol 2009;20:497–504. https://doi.org/10.1097/mol.0b013e3283319a1d.Search in Google Scholar

26. Piťha, J, Kovář, J, Blahová, T. Fasting and nonfasting triglycerides in cardiovascular and other diseases. Physiol Res 2015;64:323–30.10.33549/physiolres.933196Search in Google Scholar PubMed

27. Edwards, SH, Stribling, SL, Pyatt, SD, Kimberly, MM. Reference measurement procedure for total glycerides by isotope dilution GC-MS. Clin Chem 2012;58:768–76. https://doi.org/10.1373/clinchem.2011.177063.Search in Google Scholar PubMed

28. Centers for Disease Control and Prevention. LSP: lipids standardization program. Available from: https://www.cdc.gov/labstandards/lsp.html [Accessed 4 Apr 2022].Search in Google Scholar

29. National Institute of Standards and Technology. Standard reference material (SRM) 909c. Available from: https://www-s.nist.gov/srmors/view_detail.cfm?srm=909C [Accessed 4 Apr 2022].Search in Google Scholar

30. National Institute of Standards and Technology. Standard reference material (SRM) 1951c. Available from: https://www-s.nist.gov/srmors/view_detail.cfm?srm=1951c [Accessed 4 Apr 2022].Search in Google Scholar

31. Rifai, N, Warnick, GR, Dominiczak, MH, editors. Handbook of lipoprotein testing. Washington DC: AACC Press; 2000.Search in Google Scholar

32. Warnick, GR, Kimberly, MM, Waymack, PP, Leary, ET, Myers, GL. Standardization of measurements for cholesterol, triglycerides, and major lipoproteins. Lab Med 2008;39:481–90. https://doi.org/10.1309/6ul9rhjh1jffu4py.Search in Google Scholar

33. Wilson, PWF, Jacobson, TA, Martin, SS, Jackson, EJ, Le, NA, Davidson, MH, et al.. Lipid measurements in the management of cardiovascular diseases: practical recommendations a scientific statement from the national lipid association writing group. J Clin Lipidol 2021;15:629–48. https://doi.org/10.1016/j.jacl.2021.09.046.Search in Google Scholar PubMed

34. van Heerden, C, Magwete, A, Mabuza, D. Evaluating the need for free glycerol blanking for serum triglyceride measurements at Charlotte Maxeke Johannesburg Academic Hospital. Clin Chem Lab Med 2020;58:1257–64. https://doi.org/10.1515/cclm-2019-0991.Search in Google Scholar PubMed

35. Backes, JM, Dayspring, TD, Hoefner, DM, Contois, JH, McConnell, JP, Moriarty, PM. Identifying pseudohypertriglyceridemia in clinical practice. Clin Lipidol 2014;9:625–41. https://doi.org/10.2217/clp.14.52.Search in Google Scholar

36. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. NIH; 1995. [Online]. Available from: https://assets.speakcdn.com/Assets/2606/0e2030023_ncep-recommendations-on-lipoprotein-measurement.pdf.Search in Google Scholar

37. Nikolac, N. Lipemia: causes, interference mechanisms, detection and management. Biochem Med 2014;24:57–67. https://doi.org/10.11613/bm.2014.008.Search in Google Scholar PubMed PubMed Central

38. Godfrey, M. Classification of hyperlipidaemias. The Hyperlipidaemia Handbook. Dordrecht: Springer Netherlands; 1990.10.1007/978-94-011-3898-7Search in Google Scholar

39. Visseren, FLJ, Mach, F, Smulders, YM, Carballo, D, Koskinas, KC, Bäck, M, et al.. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227–337. https://doi.org/10.1093/eurheartj/ehab484.Search in Google Scholar PubMed

40. Wagner, AM, Perez, A, Zapico, E, Ordóñez-Llanos, J. Non-HDL cholesterol and apolipoprotein B in the dyslipidemic classification of type 2 diabetic patients. Diabetes Care 2003;26:2048–51. https://doi.org/10.2337/diacare.26.7.2048.Search in Google Scholar PubMed

41. Khan, SH, Asif, N, Ijaz, A, Manzoor, SM, Niazi, NK, Fazal, N. Status of non-HDL-cholesterol and LDL-cholesterol among subjects with and without metabolic syndrome. J Pakistan Med Assoc 2018;68:554–8.Search in Google Scholar

42. Bajaj, A, Xie, D, Cedillo-Couvert, E, Charleston, J, Chen, J, Deo, R, et al.. Lipids, apolipoproteins, and risk of atherosclerotic cardiovascular disease in persons with CKD. Am J Kidney Dis 2019;73:827–36. https://doi.org/10.1053/j.ajkd.2018.11.010.Search in Google Scholar PubMed PubMed Central

43. Rashan, MA, Dawood, OT, Al-Ani, HAA, Hassali, MA. The impact of cigarette smoking on lipid profile among iraqi smokers. Int J Collab Res Intern Med Public Health 2016;8:491–500.10.4103/0975-7406.171738Search in Google Scholar

44. Venkatesan, A, Hemalatha, A, Bobby, Z, Selvaraj, N, Sathiyapriya, V. Effect of smoking on lipid profile and lipid peroxidation in normal subjects. Indian J Physiol Pharmacol 2006;50:273–8.Search in Google Scholar

45. Quispe, R, Martin, SS, Michos, ED, Lamba, I, Blumenthal, RS, Saeed, A, et al.. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J 2021;42:4324–32. https://doi.org/10.1093/eurheartj/ehab432.Search in Google Scholar PubMed PubMed Central

46. Langlois, MR, Chapman, MJ, Cobbaert, C, Mora, S, Remaley, AT, Ros, E, et al.. Quantifying atherogenic lipoproteins: current and future challenges in the era of personalized medicine and very low concentrations of LDL cholesterol. A consensus statement from EAS and EFLM. Clin Chem 2018;64:1006–33. https://doi.org/10.1373/clinchem.2018.287037.Search in Google Scholar PubMed

47. Robinson, JG, Wang, S, Smith, BJ, Jacobson, TA. Meta-Analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease Risk. J Am Coll Cardiol 2009;53:316–22. https://doi.org/10.1016/j.jacc.2008.10.024.Search in Google Scholar PubMed

48. Liu, J, Sempos, CT, Donahue, RP, Dorn, J, Trevisan, M, Grundy, SM. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363–8. https://doi.org/10.1016/j.amjcard.2006.06.032.Search in Google Scholar PubMed

49. Liu, J, Sempos, C, Donahue, RP, Dorn, J, Trevisan, M, Grundy, SM. Joint distribution of non-HDL and LDL cholesterol and coronary heart disease risk prediction among individuals with and without diabetes. Diabetes Care 2005;28:1916–21. https://doi.org/10.2337/diacare.28.8.1916.Search in Google Scholar PubMed

50. Edwards, SH, Kimberly, MM, Pyatt, SD, Stribling, SL, Dobbin, KD, Myers, GL. Proposed serum cholesterol reference measurement procedure by gas chromatography-isotope dilution mass spectrometry. Clin Chem 2011;57:614–22. https://doi.org/10.1373/clinchem.2010.158766.Search in Google Scholar PubMed

51. Kexin, W, Yaodong, D, Wen, G, Rui, W, Jiaxin, Y, Xiaoli, L, et al.. Association of increased remnant cholesterol and the risk of coronary artery disease: a retrospective study. Front Cardiovasc Med 2021;8:1–10. https://doi.org/10.3389/fcvm.2021.740596.Search in Google Scholar PubMed PubMed Central

52. Varbo, A, Benn, M, Tybjærg-Hansen, A, Jørgensen, AB, Frikke-Schmidt, R, Nordestgaard, BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36. https://doi.org/10.1016/j.jacc.2012.08.1026.Search in Google Scholar PubMed

53. Varbo, A, Freiberg, JJ, Nordestgaard, BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem 2015;61:533–43. https://doi.org/10.1373/clinchem.2014.234146.Search in Google Scholar PubMed

54. Langlois, MR, Nordestgaard, BG. Which lipids should be analyzed for diagnostic workup and follow-up of patients with hyperlipidemias? Curr Cardiol Rep 2018;20:1–20. https://doi.org/10.1007/s11886-018-1036-1.Search in Google Scholar PubMed

55. Chen, J, Kuang, J, Tang, X, Mao, L, Guo, X, Luo, Q, et al.. Comparison of calculated remnant lipoprotein cholesterol levels with levels directly measured by nuclear magnetic resonance. Lipids Health Dis 2020;19:1–13. https://doi.org/10.1186/s12944-020-01311-w.Search in Google Scholar PubMed PubMed Central

56. Sandesara, PB, Virani, SS, Fazio, S, Shapiro, MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev 2019;40:537–57. https://doi.org/10.1210/er.2018-00184.Search in Google Scholar PubMed PubMed Central

57. Gaudet, D, Alexander, VJ, Baker, BF, Brisson, D, Tremblay, K, Singleton, W, et al.. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438–47. https://doi.org/10.1056/nejmoa1400283.Search in Google Scholar

58. Karathanasis, SK. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc Natl Acad Sci U S A 1985;82:6374–8. https://doi.org/10.1073/pnas.82.19.6374.Search in Google Scholar PubMed PubMed Central

59. Bruns, GA, Karathanasis, SK, Breslow, JL. Human apolipoprotein A-I--C-III gene complex is located on chromosome 11. Arteriosclerosis 1984;4:97–102. https://doi.org/10.1161/01.atv.4.2.97.Search in Google Scholar

60. Ebara, T, Ramakrishnan, R, Steiner, G, Shachter, NS. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E. J Clin Invest 1997;99:2672–81. https://doi.org/10.1172/jci119456.Search in Google Scholar

61. Lambert, DA, Smith, LC, Pownall, H, Sparrow, JT, Nicolas, JP, Gotto, AMJr. Hydrolysis of phospholipids by purified milk lipoprotein lipase. Effect of apoprotein CII, CIII, A and E, and synthetic fragments. Clin Chim Acta 2000;291:19–33. https://doi.org/10.1016/s0009-8981(99)00193-x.Search in Google Scholar

62. Mekki, K, Prost, J, Bouchenak, M, Remaoun, M, Belleville, J. Plasma lipoprotein lipase, hepatic lipase activities, VLDL, LDL compositions at different times of hemodialysis. Atherosclerosis 2003;169:269–77. https://doi.org/10.1016/s0021-9150(03)00011-x.Search in Google Scholar

63. Zheng, C, Khoo, C, Furtado, J, Sacks, FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation 2010;121:1722–34. https://doi.org/10.1161/circulationaha.109.875807.Search in Google Scholar

64. Sehayek, E, Eisenberg, S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway. J Biol Chem 1991;266:18259–67. https://doi.org/10.1016/s0021-9258(18)55263-7.Search in Google Scholar

65. Varbo, A, Benn, M, Nordestgaard, BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther 2014;141:358–67. https://doi.org/10.1016/j.pharmthera.2013.11.008.Search in Google Scholar

66. Olin-Lewis, K, Krauss, RM, La Belle, M, Blanche, PJ, Barrett, PHR, Wight, TN, et al.. ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res 2002;43:1969–77. https://doi.org/10.1194/jlr.m200322-jlr200.Search in Google Scholar

67. Hiukka, A, Ståhlman, M, Pettersson, C, Levin, M, Adiels, M, Teneberg, S, et al.. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes 2009;58:2018–26. https://doi.org/10.2337/db09-0206.Search in Google Scholar

68. Luc, G, Fievet, C, Arveiler, D, Evans, AE, Bard, JM, Cambien, F, et al.. Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Temoins sur ’Infarctus du Myocarde. J Lipid Res 1996;37:508–17. https://doi.org/10.1016/s0022-2275(20)37594-5.Search in Google Scholar

69. Kawakami, A, Aikawa, M, Nitta, N, Yoshida, M, Libby, P, Sacks, FM. Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase C alpha-mediated nuclear factor-kappaB activation. Arterioscler Thromb Vasc Biol 2007;27:219–25. https://doi.org/10.1161/01.atv.0000249620.68705.0d.Search in Google Scholar

70. Sakurabayashi, I, Saito, Y, Kita, T, Matsuzawa, Y, Goto, Y. Reference intervals for serum apolipoproteins A-I, A-II, B, C-II, C-III, and E in healthy Japanese determined with a commercial immunoturbidimetric assay and effects of sex, age, smoking, drinking, and Lp(a) level. Clin Chim Acta 2001;312:87–95. https://doi.org/10.1016/s0009-8981(01)00591-5.Search in Google Scholar

71. Nicolay, A, Lombard, E, Arlotto, E, Saunier, V, Lorec-Penet, AM, Lairon, D, et al.. Evaluation of new apolipoprotein C-II and apolipoprotein C-III automatized immunoturbidimetric kits. Clin Biochem 2006;39:935–41. https://doi.org/10.1016/j.clinbiochem.2006.04.021.Search in Google Scholar PubMed

72. Sandin, Å, Olofsson, C, Strålfors, A, Rajamand Ekberg, N, Brismar, K, Juntti-Berggren, L, et al.. Human apolipoprotein CIII levels; evaluation of three assay methods. Scand J Clin Lab Invest 2020;80:230–5. https://doi.org/10.1080/00365513.2020.1725976.Search in Google Scholar PubMed

73. Cobbaert, CM, Althaus, H, Begcevic Brkovic, I, Ceglarek, U, Coassin, S, Delatour, V, et al.. Towards an SI-traceable reference measurement system for seven serum apolipoproteins using bottom-up quantitative proteomics: conceptual approach enabled by cross-disciplinary/cross-sector collaboration. Clin Chem 2021;67:478–89. https://doi.org/10.1093/clinchem/hvaa239.Search in Google Scholar PubMed

74. IFCC Working Group on Apolipoproteins by Mass Spectrometry (WG-APO MS). Available from: https://www.ifcc.org/ifcc-scientific-division/sd-working-groups/wg-apo-ms [Accessed 7 Apr 2022].Search in Google Scholar

75. Borén, J, Packard, CJ, Taskinen, MR. The roles of apoC-III on the metabolism of triglyceride-rich lipoproteins in humans. Front Endocrinol 2020;11:1–10. https://doi.org/10.3389/fendo.2020.00474.Search in Google Scholar PubMed PubMed Central

76. Goldberg, RB, Chait, A. A comprehensive update on the chylomicronemia syndrome. Front Endocrinol 2020;11:1–13. https://doi.org/10.3389/fendo.2020.593931.Search in Google Scholar PubMed PubMed Central

77. Digenio, A, Dunbar, RL, Alexander, VJ, Hompesch, M, Morrow, L, Lee, RG, et al.. Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care 2016;39:1408–15. https://doi.org/10.2337/dc16-0126.Search in Google Scholar PubMed

78. Chan, DC, Nguyen, MN, Watts, GF, Barrett, PHR. Plasma apolipoprotein C-III transport in centrally obese men: associations with very low-density lipoprotein apolipoprotein B and high-density lipoprotein apolipoprotein A-I metabolism. J Clin Endocrinol Metab 2008;93:557–64. https://doi.org/10.1210/jc.2006-2676.Search in Google Scholar PubMed PubMed Central

79. Chan, DC, Watts, GF, Ooi, EMM, Ji, J, Johnson, AG, Barrett, PHR. Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008;28:1831–7. https://doi.org/10.1161/atvbaha.108.170530.Search in Google Scholar PubMed PubMed Central

80. Chan, DT, Dogra, GK, Irish, AB, Ooi, EM, Barrett, PH, Chan, DC, et al.. Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III. J Lipid Res 2009;50:2524–31. https://doi.org/10.1194/jlr.p900003-jlr200.Search in Google Scholar

81. Gaudet, D. Novel therapies for severe dyslipidemia originating from human genetics. Curr Opin Lipidol 2016;27:112–24. https://doi.org/10.1097/mol.0000000000000281.Search in Google Scholar

82. Gaudet, D, Brisson, D, Tremblay, K, Alexander, V, Singleton, W, Hughes, SG, et al.. Targeting APOC3 in the Familial chylomicronemia syndrome. N Engl J Med 2014;371:2200–6. https://doi.org/10.1056/nejmoa1400284.Search in Google Scholar

83. Van Den Broek, I, Romijn, FPHTM, Nouta, J, van der Laarse, A, Drijfhout, JW, Smit, NPM, et al.. Automated multiplex LC-MS/MS assay for quantifying serum apolipoproteins A-I , B , C-I , C-II , C-III , and E with qualitative apolipoprotein E phenotyping. Clin Chem 2016;62:188–97. https://doi.org/10.1373/clinchem.2015.246702.Search in Google Scholar

84. IFCC Working Group on Apolipoproteins by Mass Spectrometry (WG-APO MS). Update on reference materials for apolipoproteins. Available from: https://www.ifcc.org/media/478995/210519_cdc_update_who-ifcc_apomaterials_def.pdf [Accessed 9 Apr 2022].Search in Google Scholar

85. Wolska, A, Dunbar, RL, Freeman, LA, Ueda, M, Amar, MJ, Sviridov, DO, et al.. Apolipoprotein C-II: new findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis 2017:549–62. https://doi.org/10.1016/j.atherosclerosis.2017.10.025.Search in Google Scholar

86. Allan, CM, Taylor, S, Taylor, JM. Two hepatic enhancers, HCR.1 and HCR.2, coordinate the liver expression of the entire human apolipoprotein E/C-I/C-IV/C-II gene cluster. J Biol Chem 1997;272:29113–9. https://doi.org/10.1074/jbc.272.46.29113.Search in Google Scholar

87. Shachter, NS, Zhu, Y, Walsh, A, Breslow, JL, Smith, JD. Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus. J Lipid Res 1993;34:1697–707. https://doi.org/10.1016/s0022-2275(20)35732-1.Search in Google Scholar

88. McIlhargey, TL, Yang, Y, Wong, H, Hill, JS. Identification of a lipoprotein lipase cofactor-binding site by chemical cross-linking and transfer of apolipoprotein C-II-responsive lipolysis from lipoprotein lipase to hepatic lipase. J Biol Chem 2003;278:23027–35. https://doi.org/10.1074/jbc.m300315200.Search in Google Scholar

89. Hill, JS, Yang, D, Nikazy, J, Curtiss, LK, Sparrow, JT, Wong, H. Subdomain chimeras of hepatic lipase and lipoprotein lipase. Localization of heparin and cofactor binding. J Biol Chem 1998;273:30979–84. https://doi.org/10.1074/jbc.273.47.30979.Search in Google Scholar PubMed

90. AbouRjaili, G, Shtaynberg, N, Wetz, R, Costantino, T, Abela, GS. Current concepts in triglyceride metabolism, pathophysiology, and treatment. Metabolism 2010;59:1210–20. https://doi.org/10.1016/j.metabol.2009.11.014.Search in Google Scholar PubMed

91. Baggio, G, Manzato, E, Gabelli, C, Fellin, R, Martini, S, Enzi, GB, et al.. Apolipoprotein C-II deficiency syndrome. Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients. J Clin Invest 1986;77:520–7. https://doi.org/10.1172/jci112332.Search in Google Scholar

92. Curry, MD, McConathy, WJ, Fesmire, JD, Alaupovic, P. Quantitative determination of apolipoproteins C-I and C-II in human plasma by separate electroimmunoassays. Clin Chem 1981;27:543–8. https://doi.org/10.1093/clinchem/27.4.543.Search in Google Scholar

93. Fan, P, Liu, B, Fang, D, Zhang, R. Serum apolipoprotein C II, C III and E levels in 437 male healthy subjects aged 40-70 in Chengdu area. Hua Xi Yi Ke Da Xue Xue Bao 1997;28:6–9.Search in Google Scholar

94. Ueda, M, Dunbar, RL, Wolska, A, Sikora, TU, Escobar, MR, Seliktar, N, et al.. A Novel APOC2 missense mutation causing apolipoprotein C-II deficiency with severe triglyceridemia and pancreatitis. J Clin Endocrinol Metab 2017;102:1454–7. https://doi.org/10.1210/jc.2016-3903.Search in Google Scholar PubMed PubMed Central

95. Wolska, A, Reimund, M, Sviridov, DO, Amar, MJ, Remaley, AT. Apolipoprotein mimetic peptides: potential new therapies for cardiovascular diseases. Cells 2021;10:1–19.10.3390/cells10030597Search in Google Scholar PubMed PubMed Central

96. Santos-Baez, LS, Ginsberg, HN. Hypertriglyceridemia—causes, significance, and approaches to therapy. Front Endocrinol 2020;11:1–7. https://doi.org/10.3389/fendo.2020.00616.Search in Google Scholar PubMed PubMed Central

97. Ueda, M, Wolska, A, Burke, FM, Escobar, M, Walters, L, Lalic, D, et al.. Experimental therapeutics for challenging clinical care of a patient with an extremely rare homozygous APOC2 mutation. Case Rep Endocrinol 2020;2020:1–6. https://doi.org/10.1155/2020/1865489.Search in Google Scholar PubMed PubMed Central

98. Cao, J, Steffen, BT, Guan, W, Remaley, AT, McConnell, JP, Palamalai, V, et al.. A comparison of three apolipoprotein B methods and their associations with incident coronary heart disease risk over a 12-year follow-up period: the Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol 2018;12:300–4. https://doi.org/10.1016/j.jacl.2017.12.013.Search in Google Scholar PubMed

99. Delatour, V, Clouet-Foraison, N, Gaie-Levrel, F, Marcovina, SM, Hoofnagle, AN, Kuklenyik, Z, et al.. Comparability of lipoprotein particle number concentrations across ES-DMA, NMR, LC-MS/MS, immunonephelometry, and VAP: in search of a candidate reference measurement procedure for apoB and non-HDL-P standardization. Clin Chem 2018;64:1485–95. https://doi.org/10.1373/clinchem.2018.288746.Search in Google Scholar PubMed

100. Sakai, N, Uchida, Y, Ohashi, K, Hibuse, T, Saika, Y, Tomari, Y, et al.. Measurement of fasting serum apoB-48 levels in normolipidemic and hyperlipidemic subjects by ELISA. J Lipid Res 2003;44:1256–62. https://doi.org/10.1194/jlr.m300090-jlr200.Search in Google Scholar PubMed

101. Meyers, CD, Tremblay, K, Amer, A, Chen, J, Jiang, L, Gaudet, D. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015;14:1–9. https://doi.org/10.1186/s12944-015-0006-5.Search in Google Scholar PubMed PubMed Central

102. Hegele, RA, Borén, J, Ginsberg, HN, Arca, M, Averna, M, Binder, CJ, et al.. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol 2020;8:50–67. https://doi.org/10.1016/S2213-8587(19)30264-5.Search in Google Scholar

103. Shah, AS, Wilson, DP. Genetic disorders causing hypertriglyceridemia in children and adolescents. Endotext 2000;10:1–6.Search in Google Scholar

104. Hegele, RA, Ginsberg, HN, Chapman, MJ, Nordestgaard, BG, Kuivenhoven, JA, Averna, M, et al.. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2:655–66. https://doi.org/10.1016/s2213-8587(13)70191-8.Search in Google Scholar

105. Meyer, E, Westerveld, HT, De Ruyter-Meijstek, FC, Van Greevenbroek, MMJ, Rienks, R, Van Rijn, HJM, et al.. Abnormal postprandial apolipoprotein B-48 and triglyceride responses in normolipidemic women with greater than 70% stenotic coronary artery disease: a case-control study. Atherosclerosis 1996;124:221–35. https://doi.org/10.1016/0021-9150(96)05832-7.Search in Google Scholar

106. Tian, J, Chen, H, Liu, P, Wang, C, Chen, Y. Fasting apolipoprotein B48 is associated with large artery atherosclerotic stroke: a case-control study. Sci Rep 2019;9:1–6. https://doi.org/10.1038/s41598-019-40385-0.Search in Google Scholar PubMed PubMed Central

107. Masuda, D, Sugimoto, T, Ken-Ichi, T, Inagaki, M, Nakatani, K, Yuasa-Kawase, M, et al.. Correlation of fasting serum apolipoprotein B-48 with coronary artery disease prevalence. Eur J Clin Invest 2012;42:992–9. https://doi.org/10.1111/j.1365-2362.2012.02687.x.Search in Google Scholar PubMed

108. Mori, K, Ishida, T, Yasuda, T, Monguchi, T, Sasaki, M, Kondo, K, et al.. Fasting serum concentration of apolipoprotein B48 represents residual risks in patients with new-onset and chronic coronary artery disease. Clin Chim Acta 2013;421:51–6. https://doi.org/10.1016/j.cca.2013.02.005.Search in Google Scholar PubMed

109. Alipour, A, Valdivielso, P, Elte, JWF, Janssen, HW, Rioja, J, van der Meulen, N, et al.. Exploring the value of apoB48 as a marker for atherosclerosis in clinical practice. Eur J Clin Invest 2012;42:702–8. https://doi.org/10.1111/j.1365-2362.2011.02635.x.Search in Google Scholar PubMed

110. Tanimura, K, Nakajima, Y, Nagao, M, Ishizaki, A, Kano, T, Harada, T, et al.. Association of serum apolipoprotein B48 level with the presence of carotid plaque in type 2 diabetes mellitus. Diabetes Res Clin Pract 2008;81:338–44. https://doi.org/10.1016/j.diabres.2008.04.028.Search in Google Scholar PubMed

111. Krysa, JA, Vine, DF, Beilin, LJ, Burrows, S, Huang, RC, Mori, TA, et al.. ApoB48-remnant lipoproteins are associated with increased cardiometabolic risk in adolescents. Atherosclerosis 2020;302:20–6. https://doi.org/10.1016/j.atherosclerosis.2020.04.021.Search in Google Scholar PubMed

112. Nakajima, K, Nagamine, T, Fujita, MQ, Ai, M, Tanaka, A, Schaefer, E. Apolipoprotein B-48: a unique marker of chylomicron metabolism. Adv Clin Chem 2014;64:117–77. https://doi.org/10.1016/b978-0-12-800263-6.00003-3.Search in Google Scholar

113. Noble, RP. Electrophoretic separation of 1. plasma lipoproteins in agarose gel. J Lipid Res 1968;9:693–700. https://doi.org/10.1016/s0022-2275(20)42680-x.Search in Google Scholar

Received: 2022-03-02
Accepted: 2022-04-29
Published Online: 2022-06-10
Published in Print: 2022-07-26

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 25.4.2024 from https://www.degruyter.com/document/doi/10.1515/cclm-2022-0189/html
Scroll to top button