Metabolic pathway of LDL, HDL and TG, including diseases (WP4522)

Homo sapiens

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This pathway shows genetic disorders related to lipoprotein metabolism. Two plasmalipoproteins, LDL and HDL, and one plasma lipid, triglyceride (TG), play an important role in this pathway. Hydrophobic lipids and fat-soluble vitamins are normally transported to the site of their uptake by transporters called lipoproteins, and any deregulation of the plasma concentrations of these proteins can cause dyslipidemias. Disorders resulting from an enzyme deficiency are highlighted in pink. More details on the composition of the various lipoproteins in this pathway are visualised in [https://www.wikipathways.org/index.php/Pathway:WP3601]. This pathway was inspired by Chapter 43 of the book of Blau (ISBN 3642403360 (978-3642403361)).

Authors

Ingebude , Denise Slenter , Lobke Meels , Martina Summer-Kutmon , Egon Willighagen , Irene Hemel , Friederike Ehrhart , Finterly Hu , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Pathway Ontology

disease pathway familial combined hyperlipidemia pathway altered lipoprotein metabolic pathway triacylglycerol metabolic pathway lipoprotein metabolic pathway

Disease Ontology

familial lipoprotein lipase deficiency Tangier disease hypobetalipoproteinemia autosomal recessive hypercholesterolemia abetalipoproteinemia familial apolipoprotein C-II deficiency cholesterol-ester transfer protein deficiency familial combined hyperlipidemia

Participants
Query Drugst.One

Label Type Compact URI Comment
Cholesterol Metabolite chebi:16113
Cyclic fatty acids Metabolite chebi:59238
VLDL Metabolite chebi:39027 Very low-density lipoprotein (VLDL) is one of the two main TG (triglyceride or triacylglycerol) carrying lipoproteins, which are spheroidal macromolecular complexes responsible for transporting lipids through plasma.
IDL Metabolite chebi:132933 Itermediate-density lipoprotein (IDL), physiologically a short lived species, containd around equimolar amounts of cholesterol and Triglycerides (TG).
LDL Metabolite chebi:39026 Low-density lipoprotein (LDL) is one of the two main cholesterol carrying lipoproteins, which are spheroidal macromolecular complexes responsible for transporting lipids through plasma.
LPL GeneProduct ensembl:ENSG00000175445
LCAT GeneProduct ensembl:ENSG00000213398 AKA Lecithin-cholesterol acyl transferase
LIPC GeneProduct uniprot:P11150 HL; EC 3.1.1.3
LIPG GeneProduct uniprot:Q9Y5X9 HL; EC 3.1.1.3 aka LIPC
CETP GeneProduct ensembl:ENSG00000087237
MTTP GeneProduct uniprot:P55157 MTP; 'Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. Required for the secretion of plasma lipoproteins that contain apolipoprotein B.' [https://www.uniprot.org/uniprot/P55157]
PCSK9 GeneProduct ensembl:ENSG00000169174
ABCA1 GeneProduct ensembl:ENSG00000165029
MTP GeneProduct uniprot:P55157 'Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. Required for the secretion of plasma lipoproteins that contain apolipoprotein B.' [https://www.uniprot.org/uniprot/P55157]
LDLR Protein ensembl:ENSG00000130164
SCARB1 Protein uniprot:Q8WTV0 SR-B1; AKA SCARB1; Receptor for HDL, mediating selective uptake of cholesteryl ether and HDL-dependent cholesterol efflux.
LDLRAP1 Protein uniprot:Q5SW96 AKA Low density lipoprotein receptor adapter protein 1; ARH1
'Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytocis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members.' [https://www.uniprot.org/uniprot/Q5SW96]
ANXA2 Protein uniprot:P07355 Annexin A2
LDLR Protein uniprot:P01130 LDL-receptor
APOC2 Protein uniprot:P02655 C-II; AKA Apolipoprotein C2; cofactor for lipoprotein lipase (LPL) enzyme.
Remnant receptor Protein interpro:IPR038003 'The chylomicron remnant receptor accepts apoE as a ligand. Chylomicron remnants are removed from the circulation exclusively by the liver, probably because these large complexes can penetrate the unique sinusoidal vascular space. The multifunctional, α2-macroglobulin/LDL receptor-related protein (LRP) is the chylomicron remnant receptor' [https://doi.org/10.1016/B978-1-4160-6189-2.00072-X]
apo B-48 Protein uniprot:P04114 'Apolipoprotein B(apo B) occurs in the plasma in 2 main isoforms, ApoB48 and ApoB100. ApoB48 is generated when a stop codon (UAA) is created by RNA editing. As a result of the RNA editing, ApoB48 and ApoB100 share a common N-terminal sequence, but ApoB48 lacks ApoB100's C-terminal LDL receptor binding region. In fact, ApoB48 is so called because it constitutes 48% of the sequence for ApoB100. ApoB 48 is a unique protein to chylomicrons from the small intestine. After most of the lipids in the chylomicron have been absorbed, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.' [https://en.wikipedia.org/wiki/Apolipoprotein_B]
Synthesized in small intestine.
Transcript ID: ENST00000233242.4
APOE Protein uniprot:P02649 E; AKA APo E, a ligand for receptor mediated endocytosis.
B100 Protein uniprot:P04114 'Apoprotein B100 (ApoB-100) is embedded in the outer phospholipid layer of LDL particles.' [https://en.wikipedia.org/wiki/LDL_receptor]
Synthesized in liver.
apo B-48 Protein uniprot:P04114 'Apolipoprotein B(apo B) occurs in the plasma in 2 main isoforms, ApoB48 and ApoB100. ApoB48 is generated when a stop codon (UAA) is created by RNA editing. As a result of the RNA editing, ApoB48 and ApoB100 share a common N-terminal sequence, but ApoB48 lacks ApoB100's C-terminal LDL receptor binding region. In fact, ApoB48 is so called because it constitutes 48% of the sequence for ApoB100. ApoB 48 is a unique protein to chylomicrons from the small intestine. After most of the lipids in the chylomicron have been absorbed, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.' [https://en.wikipedia.org/wiki/Apolipoprotein_B]
Synthesized in small intestine.
APOA1 Protein uniprot:P02647 A-I; AKA Apo A-I; activator of lecithin-cholesterol acyl transferase (LCAT).
APOA2 Protein uniprot:P02652 A-II; AKA Apolipoprotein A-II

References

  1. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
  2. A new type of familial hypercholesterolaemia. Higgins MJ, Lecamwasam DS, Galton DJ. Lancet. 1975 Oct 18;2(7938):737–40. PubMed Europe PMC Scholia
  3. Familial hyperalphalipoproteinemia. Glueck CJ, Fallat RW, Millett F, Steiner PM. Arch Intern Med. 1975 Aug;135(8):1025–8. PubMed Europe PMC Scholia
  4. The lipoprotein abnormality in Tangier disease: quantitation of A apoproteins. Assmann G, Smootz E, Adler K, Capurso A, Oette K. J Clin Invest. 1977 Mar;59(3):565–75. PubMed Europe PMC Scholia
  5. Isolation and characterization of an abnormal high density lipoprotein in Tangier Diesase. Assmann G, Herbert PN, Fredrickson DS, Forte T. J Clin Invest. 1977 Jul;60(1):242–52. PubMed Europe PMC Scholia
  6. Defective enzyme protein in lipoprotein lipase deficiency. Auwerx JH, Babirak SP, Fujimoto WY, Iverius PH, Brunzell JD. Eur J Clin Invest. 1989 Oct;19(5):433–7. PubMed Europe PMC Scholia
  7. ApoE deficiency: markedly decreased levels of cellular ApoE mRNA. Anchors JM, Gregg RE, Law SW, Brewer HB Jr. Biochem Biophys Res Commun. 1986 Jan 29;134(2):937–43. PubMed Europe PMC Scholia
  8. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, et al. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6919–23. PubMed Europe PMC Scholia
  9. An incomplete form of familial lipoprotein lipase deficiency presenting with type I hyperlipoproteinemia. Berger GM. Am J Clin Pathol. 1987 Sep;88(3):369–73. PubMed Europe PMC Scholia
  10. Apolipoprotein C-II deficiency syndrome. Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients. Baggio G, Manzato E, Gabelli C, Fellin R, Martini S, Enzi GB, et al. J Clin Invest. 1986 Feb;77(2):520–7. PubMed Europe PMC Scholia
  11. Evidence for deficiency of high density lipoprotein lecithin: cholesterol acyltransferase activity (alpha-LCAT) in fish eye disease. Carlson LA, Holmquist L. Acta Med Scand. 1985;218(2):189–96. PubMed Europe PMC Scholia
  12. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. J Lipid Res. 1983 Feb;24(2):147–55. PubMed Europe PMC Scholia
  13. Detection of heterozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Frohlich J, Hon K, McLeod R. Am J Hum Genet. 1982 Jan;34(1):65–72. PubMed Europe PMC Scholia
  14. Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kuksis A, Kakis G, et al. Atherosclerosis. 1982 Nov;45(2):161–79. PubMed Europe PMC Scholia
  15. Familial lecithin-cholesterol acyltransferase: identification of heterozygotes with half-normal enzyme activity and mass. Albers JJ, Chen C, Adolphson JL. Hum Genet. 1981;58(3):306–9. PubMed Europe PMC Scholia
  16. Cadiovascular complications of homozygous familial hypercholesterolaemia. Allen JM, Thompson GR, Myant NB, Steiner R, Oakley CM. Br Heart J. 1980 Oct;44(4):361–8. PubMed Europe PMC Scholia
  17. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase. Rehberg EF, Samson-Bouma ME, Kienzle B, Blinderman L, Jamil H, Wetterau JR, et al. J Biol Chem. 1996 Nov 22;271(47):29945–52. PubMed Europe PMC Scholia
  18. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. Haemmerle G, Zimmermann R, Hayn M, Theussl C, Waeg G, Wagner E, et al. J Biol Chem. 2002 Feb 15;277(7):4806–15. PubMed Europe PMC Scholia
  19. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia. Al-Kateb H, Bähring S, Hoffmann K, Strauch K, Busjahn A, Nürnberg G, et al. Circ Res. 2002 May 17;90(9):951–8. PubMed Europe PMC Scholia
  20. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Nat Genet. 2003 Jun;34(2):154–6. PubMed Europe PMC Scholia
  21. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al. N Engl J Med. 2004 Apr 8;350(15):1505–15. PubMed Europe PMC Scholia
  22. Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein. Mishra SK, Keyel PA, Edeling MA, Dupin AL, Owen DJ, Traub LM. J Biol Chem. 2005 May 13;280(19):19270–80. PubMed Europe PMC Scholia
  23. Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases. Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HMK. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2126–31. PubMed Europe PMC Scholia
  24. Molecular biology of PCSK9: its role in LDL metabolism. Horton JD, Cohen JC, Hobbs HH. Trends Biochem Sci. 2007 Feb;32(2):71–7. PubMed Europe PMC Scholia
  25. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, et al. J Biol Chem. 2008 Jan 25;283(4):2363–72. PubMed Europe PMC Scholia
  26. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. Kathiresan S, Myocardial Infarction Genetics Consortium. N Engl J Med. 2008 May 22;358(21):2299–300. PubMed Europe PMC Scholia
  27. Plasma lipoproteins: genetic influences and clinical implications. Hegele RA. Nat Rev Genet. 2009 Feb;10(2):109–21. PubMed Europe PMC Scholia
  28. Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans. Brunham LR, Tietjen I, Bochem AE, Singaraja RR, Franchini PL, Radomski C, et al. Clin Genet. 2011 Jun;79(6):575–81. PubMed Europe PMC Scholia
  29. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. Di Filippo M, Créhalet H, Samson-Bouma ME, Bonnet V, Aggerbeck LP, Rabès JP, et al. J Lipid Res. 2012 Mar;53(3):548–55. PubMed Europe PMC Scholia
  30. Studies on the substrate and stereo/regioselectivity of adipose triglyceride lipase, hormone-sensitive lipase, and diacylglycerol-O-acyltransferases. Eichmann TO, Kumari M, Haas JT, Farese RV Jr, Zimmermann R, Lass A, et al. J Biol Chem. 2012 Nov 30;287(49):41446–57. PubMed Europe PMC Scholia
  31. Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. Khatun I, Walsh MT, Hussain MM. J Lipid Res. 2013 Jun;54(6):1541–9. PubMed Europe PMC Scholia
  32. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. Lee J, Hegele RA. J Inherit Metab Dis. 2014 May;37(3):333–9. PubMed Europe PMC Scholia
  33. Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9. Ly K, Saavedra YGL, Canuel M, Routhier S, Desjardins R, Hamelin J, et al. J Biol Chem. 2014 Jun 20;289(25):17732–46. PubMed Europe PMC Scholia
  34. Novel missense MTTP gene mutations causing abetalipoproteinemia. Miller SA, Burnett JR, Leonis MA, McKnight CJ, van Bockxmeer FM, Hooper AJ. Biochim Biophys Acta. 2014 Oct;1842(10):1548–54. PubMed Europe PMC Scholia
  35. Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function. Walsh MT, Iqbal J, Josekutty J, Soh J, Di Leo E, Özaydin E, et al. Circ Cardiovasc Genet. 2015 Oct;8(5):677–87. PubMed Europe PMC Scholia
  36. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, et al. Science. 2016 Mar 11;351(6278):1166–71. PubMed Europe PMC Scholia
  37. Current trends in oxysterol research. Griffiths WJ, Abdel-Khalik J, Hearn T, Yutuc E, Morgan AH, Wang Y. Biochem Soc Trans. 2016 Apr 15;44(2):652–8. PubMed Europe PMC Scholia
  38. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. N Engl J Med. 2017 Jul 20;377(3):211–21. PubMed Europe PMC Scholia