Lipoproteins were not created by nature to cause atherosclerosis. Endogenous lipoprotein metabolism. A contemporaneous and comprehensive review for the clinician.
Main Article Content
Abstract
Aim and scope: This review is intended to update the knowledge, but above all, to understand the difference between "normal" level vs. biological level of LDL cholesterol (LDL-C) and the physiology of the metabolism of lipoproteins with apoprotein B100 (LP-apoB100). Such medical knowledge is fundamental before introducing to the world of dyslipidemia, atherosclerosis, and pharmacotherapeutics.
Unfortunately, the teaching of the enunciated concepts -as a starting point for basic knowledge- is frequently mixed with multiple related topics, among them: the pathophysiology analysis of LP-apoB100 metabolism, that is, of dyslipidemias; the description of transgenic animal models for their study; Mendelian randomization studies of the correlation between certain genetic patterns or single nucleotide polymorphism with specific dyslipidemias and atherosclerotic cardiovascular disease (ASCVD), the study at different levels of atherosclerosis -main consequence of the abnormal metabolism of LP-apoB100- and finally, the treatment of atherogenic dyslipidemias, atherosclerosis, and ASCVD.
Hence, teaching these concepts is complex, and therefore, also the learning by the non-specialist physician of these priority chapters in modern medicine. This review is premised on the following sentence: “LP-apoB100 were not created by nature to cause atherosclerosis”.
In this contemporary review we will analyze current knowledge on: the physiological value of LP-apoB100 with an emphasis on LDL, metabolism of LP-apoB100 (assembly and secretion of VLDL by the hepatocyte, circulatory transformation of VLDL to IDL, circulatory/hepatic transformation of IDL to LDL and hepatobiliary elimination of LDL) and finally LDL oxidation and elimination by reverse transport.
As Goldstein and Brown anticipated in the 1970s: "only by understanding the metabolism of LP-apoB100 will we be able to develop drugs to treat hypercholesterolemia and reduce its implicit atherosclerotic cardiovascular risk."
Keywords:
Lipoproteins, atherosclerosis, Endogenous lipoprotein metabolism, review for the clinician
Article Details
How to Cite
MORALES-VILLEGAS, Enrique C.; CASTILLO-NÚÑEZ, Yulino; BADIMON, Juan José.
Lipoproteins were not created by nature to cause atherosclerosis. Endogenous lipoprotein metabolism. A contemporaneous and comprehensive review for the clinician..
Medical Research Archives, [S.l.], v. 11, n. 9, oct. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4387>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i9.4387.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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3. Calvert GD. Mammalians low density lipoproteins. In Day CE, Levy RS (eds). Low Density Lipoproteins. New York. Plenum Press. 1976: pp 281-319.
4. Kwiterovich PO Jr, Levy RI, Fredrickson DS. Neonatal diagnosis of familial type-II hyperlipoproteinemia. Lancet. 1973: i: 118-122.
5. Keys A. Coronary heart disease: the global picture. Atherosclerosis. 1975; 22:149-192.
6. Reichl D, Myant NB, Brown MS et al. Biologically active low-density lipoprotein in human peripheral lymph. J Clin Invest. 1978; 61:64-71.
7. Bilheimer DW, Stone NJ, Grundy SM. Metabolic studies in familial hypercholesterolemia: evidence for a gene-dosage effect in vivo. J Clin Invest. 1979; 64:524-533.
8. Kovanen PT, Bilheimer DW, Goldstein JL et al. Regulatory role for hepatic low lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci USA. 1981; 78:1194-1198.
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12. Steinberg D, Witztum JL. History of discovery. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010; 30:2311-2316.
13. APOB apolipoprotein B [Homo sapiens (human)] - Gene - NCBI (nih.gov)
14. Borén J, Taskinen MR, Björson E, Packard CJ. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nature Reviews Cardiology. DOI: 10.1038/s41569-022-00676-y.
15. Duran EK, Pradhan AD. Triglyceride-rich lipoprotein remnants and cardiovascular disease. Clin Chem. 2021; 67:183-287.
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39. Goldstein JL, Brown MS. Binding and degradation of low-density lipoproteins by cultured human fibroblasts: comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974; 249:5153-5162.
40. Endo A, Kuroda M and Tsujita Y. ML-236A, ML-236B and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium Citrinum. J Antibiotics. 1976; 26:1346.
41. Endo A, Kuroda M and Tanzawa K. Competitive inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase by ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS. 1976. Lett 72:323.
42. Tsujita Y, Kuroda M, Tanzawa K, Kitano N and Endo A. Hypocholesterolemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Atherosclerosis. 1979; 32:307.
43. Kuroda M, Tsujita, Tanzawa K and Endo A. Hypocholesterolemic effects in monkeys of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Lipids. 1979; 14:585.
44. Yamamoto A, Endo A, Kitano Y et al. Two Japanese kindred of familial hypercholesterolemia including homozygous cases. A report of cases and studies on serum lipoproteins and enzymes. Jap J Med. 1978; 17:230.
45. LDLR low density lipoprotein receptor [Homo sapiens (human)] - Gene - NCBI (nih.gov).
46.- HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens (human)] - Gene - NCBI (nih.gov).
47. Adams CM, Reitz J, DeBrabander JK et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanism, both involving SCAP and Insigns. J Biol Chem. 2004; 279:52772-52780.
48. Schneider WJ, Beisegel U, Goldstein JL et al. Purification of the low-density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight. J Biol Chem. 1982; 257: 2664-2673.
49. Yamamoto T, Davis CG, Brown MS et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984; 39:27-38.
50. Südhof TC, Goldstein JL, Brown MS et al. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985:228:815-822.
51. Kleber ME, Delgado GE, Márz W. LDL receptor traffic; in the fast lane. Eur J Cardiol. 2020; 41:1054-56. DOI: 10.1093/eurheartj/ ehz866.
52. LRP1 LDL receptor related protein 1 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
53. Seidah NG, Benjannet S, Wickham L et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 2003; 100:928-933.
54. Seidah NG, Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med (Berl). 2007; 85:685-696.
55. PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
56. Morales-Villegas E. In Inhibiendo a la PCSK9. La era de los anticuerpos monoclonales. 1ª Edición 2016. Editorial Atheros-CIC. ISBN: 978-607-00-9678-5.
57. Lopez D. PCSK9: An enigmatic protease. Biochimica and Biophysica Acta. 2008; 1781: 184-191.
58. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012; 11:367-383.
59. Seidah NG, Sadr MS, Chrétien M et al. The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J Biol Chem. 2013; 288:21473-21481.
60. Seidah NG, Awan Z, Chétien M and Mbikay M. PCSK9. A key modulator of cardiovascular health. Circulation Res. 2014. Published online: http//circres.ahajournals.org. DOI: 10.1161/CIRCRESAHA.114.301621.
61. Benjannet S, Rhainds D, Essalmani R et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low-density lipoprotein receptor and LDL-cholesterol. J Biol Chem. 2004; 279:48865-48875.
62. Zhang DM, Lagace TA, Garuti R et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low-density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007; 282:18602-18612.
63. Tavori H, Fan D, Blakemore JL et al. Serum PCSK9 and cell surface LDL-R: Evidence for a reciprocal regulation. Circulation. 2013; 127: 2403-2413.
64. Jeong HJ, Lee HS, Kim KS et al. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 2008; 49:399-409.
65. Morales-Villegas E. PCSK9 and LDLR. The yin-yang in the cellular uptake of cholesterol. Curr Hyperten Rev. 2013; 9:310-323.
66. Nassoury N, Blasiole DA, Tebon Oler A et al. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic. 2007; 8:718-732.
67. Morales-Villegas E. In Endotelio, aterotrombosis y estatinas. 1ª Edición 2011. Editorial Atheros CIC. ISBN: 978-607-00-3781-8.
68. Morales-Villegas E. In Cardio-Lipidología. Lipidología con enfoque cardiovascular. 1ª Edición 2012. Editorial Atheros-CIC. ISBN: 978-607-00-5669-7.
2. Mills GL, Taylaur CE. The distribution and composition of serum lipoproteins in eighteen animals. Comp Biochem Physiol. 1971; 40B:489-501.
3. Calvert GD. Mammalians low density lipoproteins. In Day CE, Levy RS (eds). Low Density Lipoproteins. New York. Plenum Press. 1976: pp 281-319.
4. Kwiterovich PO Jr, Levy RI, Fredrickson DS. Neonatal diagnosis of familial type-II hyperlipoproteinemia. Lancet. 1973: i: 118-122.
5. Keys A. Coronary heart disease: the global picture. Atherosclerosis. 1975; 22:149-192.
6. Reichl D, Myant NB, Brown MS et al. Biologically active low-density lipoprotein in human peripheral lymph. J Clin Invest. 1978; 61:64-71.
7. Bilheimer DW, Stone NJ, Grundy SM. Metabolic studies in familial hypercholesterolemia: evidence for a gene-dosage effect in vivo. J Clin Invest. 1979; 64:524-533.
8. Kovanen PT, Bilheimer DW, Goldstein JL et al. Regulatory role for hepatic low lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci USA. 1981; 78:1194-1198.
9. Cohen J, Pertsemlidis A, Kotowski IK/Hobbs HH et al. Low LDL cholesterol in subjects of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics. 2005; 37:161-165
10. Cohen J, Boerwinkle E, Mosley TH and Hobbs HH y cols. Sequence variations in PCSK9, Low LDL and Protection against Coronary Heart Disease. N Engl J Med. 2006; 354:1264-1272.
11. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation. 2008; 118:672-677.
12. Steinberg D, Witztum JL. History of discovery. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010; 30:2311-2316.
13. APOB apolipoprotein B [Homo sapiens (human)] - Gene - NCBI (nih.gov)
14. Borén J, Taskinen MR, Björson E, Packard CJ. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nature Reviews Cardiology. DOI: 10.1038/s41569-022-00676-y.
15. Duran EK, Pradhan AD. Triglyceride-rich lipoprotein remnants and cardiovascular disease. Clin Chem. 2021; 67:183-287.
16. Ginsberg HN, Packard CJ, Chapman MJ 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; 00:1-21. DOI: 10.1093/eurheartj/ehab551.
17. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2022; 41:99-109. DOI: 10.1093/eurheartj /ehz785.
18. ACAT2 acetyl-CoA acetyltransferase 2 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
19. MTTP microsomal triglyceride transfer protein [Homo sapiens (human)] - Gene - NCBI (nih.gov).
20. APOE apolipoprotein E [Homo sapiens (human)] - Gene - NCBI (nih.gov).
21. APOC1 apolipoprotein C1 [Homo sapiens (human)] - Gene - NCBI (nih.gov)
22. Rouland A, Masson D, Lagrost L et al. Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a Systematic review. Cardiovasc Diabetol. 2022; 21:272. DOI: 10.1186/s12933-022-01703-5.
23. APOC2 apolipoprotein C2 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
24. APOC3 apolipoprotein C3 [Homo sapiens (human)] - Gene - NCBI (nih.gov),
25. LPL lipoprotein lipase [Homo sapiens (human)] - Gene - NCBI (nih.gov)
26. Basu D, Goldberg IJ. Regulation of lipoprotein lipase mediated lipolysis of triglycerides. Curr Opin Lipidol. 2020; 31:154-160. DOI: 10.1097/MOL-0000000000000676.
27. APOA5 apolipoprotein A5 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
28. Sylvers-Davie KL and Davies BSJ. Regulation of lipoprotein metabolism by ANGPL3, ANGPL4, and ANGPL8. Am J Physiol Endocrinol Metab. 2021; 321; E493-508. DOI: 10.1152/ajpendo.00195.2021.
29. Ginsberg HN and Goldberg IJ. Broadening the scope on dyslipidemia therapy by targeting APOC3 and ANGPL3. Arterioscler Thromb Vasc Biol. 2023; 43:00-00. DOI: 10.1161/ATVBAHA.122.317966.
30. ANGPTL3 angiopoietin like 3 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
31. Adam RC, Mintah IJ, Alexa-Braun CA et al. Angiopoyetin-like 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res. 2020; 61:1271-1286.
32. Wu L, Soundarapandian MM, Castoreno AB et al. LDL-cholesterol reduction by ANGPL3 inhibition in mice is dependent on endothelial lipase. Circulation Res. 2020; 127:1112-1114. DOI: 10.1161/CIRCRESAHA.120.317128.
33. ANGPTL4 angiopoietin like 4 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
34. ANGPTL8 angiopoietin like 8 [Homo sapiens (human)] - Gene - NCBI (nih.gov),
35. Zhang R. The ANGPL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biol. 2016; 6:150272. DOI: 10.1098/rsob.
36. LIPC lipase C, hepatic type [Homo sapiens (human)] - Gene - NCBI (nih.gov).
37. Goldstein JL, Brown MS. History of discovery. The LDL receptor. Arterioscler Thromb Vasc Biol. 2019; 29:431-438.
38. Brown MS, Goldstein JL. A Receptor-Mediated Pathway for Cholesterol Homeostasis. Nobel Lecture. 9 December 1985. Nobelprize.org.
39. Goldstein JL, Brown MS. Binding and degradation of low-density lipoproteins by cultured human fibroblasts: comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974; 249:5153-5162.
40. Endo A, Kuroda M and Tsujita Y. ML-236A, ML-236B and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium Citrinum. J Antibiotics. 1976; 26:1346.
41. Endo A, Kuroda M and Tanzawa K. Competitive inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase by ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS. 1976. Lett 72:323.
42. Tsujita Y, Kuroda M, Tanzawa K, Kitano N and Endo A. Hypocholesterolemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Atherosclerosis. 1979; 32:307.
43. Kuroda M, Tsujita, Tanzawa K and Endo A. Hypocholesterolemic effects in monkeys of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Lipids. 1979; 14:585.
44. Yamamoto A, Endo A, Kitano Y et al. Two Japanese kindred of familial hypercholesterolemia including homozygous cases. A report of cases and studies on serum lipoproteins and enzymes. Jap J Med. 1978; 17:230.
45. LDLR low density lipoprotein receptor [Homo sapiens (human)] - Gene - NCBI (nih.gov).
46.- HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens (human)] - Gene - NCBI (nih.gov).
47. Adams CM, Reitz J, DeBrabander JK et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanism, both involving SCAP and Insigns. J Biol Chem. 2004; 279:52772-52780.
48. Schneider WJ, Beisegel U, Goldstein JL et al. Purification of the low-density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight. J Biol Chem. 1982; 257: 2664-2673.
49. Yamamoto T, Davis CG, Brown MS et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984; 39:27-38.
50. Südhof TC, Goldstein JL, Brown MS et al. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985:228:815-822.
51. Kleber ME, Delgado GE, Márz W. LDL receptor traffic; in the fast lane. Eur J Cardiol. 2020; 41:1054-56. DOI: 10.1093/eurheartj/ ehz866.
52. LRP1 LDL receptor related protein 1 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
53. Seidah NG, Benjannet S, Wickham L et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 2003; 100:928-933.
54. Seidah NG, Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med (Berl). 2007; 85:685-696.
55. PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] - Gene - NCBI (nih.gov).
56. Morales-Villegas E. In Inhibiendo a la PCSK9. La era de los anticuerpos monoclonales. 1ª Edición 2016. Editorial Atheros-CIC. ISBN: 978-607-00-9678-5.
57. Lopez D. PCSK9: An enigmatic protease. Biochimica and Biophysica Acta. 2008; 1781: 184-191.
58. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012; 11:367-383.
59. Seidah NG, Sadr MS, Chrétien M et al. The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J Biol Chem. 2013; 288:21473-21481.
60. Seidah NG, Awan Z, Chétien M and Mbikay M. PCSK9. A key modulator of cardiovascular health. Circulation Res. 2014. Published online: http//circres.ahajournals.org. DOI: 10.1161/CIRCRESAHA.114.301621.
61. Benjannet S, Rhainds D, Essalmani R et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low-density lipoprotein receptor and LDL-cholesterol. J Biol Chem. 2004; 279:48865-48875.
62. Zhang DM, Lagace TA, Garuti R et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low-density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007; 282:18602-18612.
63. Tavori H, Fan D, Blakemore JL et al. Serum PCSK9 and cell surface LDL-R: Evidence for a reciprocal regulation. Circulation. 2013; 127: 2403-2413.
64. Jeong HJ, Lee HS, Kim KS et al. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 2008; 49:399-409.
65. Morales-Villegas E. PCSK9 and LDLR. The yin-yang in the cellular uptake of cholesterol. Curr Hyperten Rev. 2013; 9:310-323.
66. Nassoury N, Blasiole DA, Tebon Oler A et al. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic. 2007; 8:718-732.
67. Morales-Villegas E. In Endotelio, aterotrombosis y estatinas. 1ª Edición 2011. Editorial Atheros CIC. ISBN: 978-607-00-3781-8.
68. Morales-Villegas E. In Cardio-Lipidología. Lipidología con enfoque cardiovascular. 1ª Edición 2012. Editorial Atheros-CIC. ISBN: 978-607-00-5669-7.