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

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1821LiverIntestineCholesterol poolCellAbetalipoproteinemia (MTP)19, 26ARH LDL receptorLactosylceramideRosuvastatin calciumIDLRemnant receptorCyclic fatty acidslysoPC a C18:2HL ABCA1(24S)-24,25-epoxycholesterolLPLLDLPCSK9Q9Y5X9MethylnorethindroneSR-B1RemnantVLDLLPLHypobetalipoproteinemia (APOB)5Lipoprotein lipase deficiency (LPL)20, 22Apolipoprotein C2 deficiency (APOC2)Dysbetalipoproteinemia (APOE)172515Hepatic lipase deficiency (LIPC)1Familial hypercholesterolemia heterozygous (LDLR)3Familial hypercholesterolemia homozygous (LDLR)Autosomal recessive hypercholesterolemia (ARH)3Cholesteryl ester transfer protein deficiency (CETP)10Tangier disease (ABCA1)2, 24Familial LCAT deficiency (partial)9, 237Familial LCAT deficiency (complete)4, 6Apolipoprotein A-1 deficiency (APOA1)16Scavenger receptor B1 deficiency (SCARB1)8Autosomal dominant hypercholesterolemiaPCSK9 deficiency with low LDL12Abetalipoproteinemia (MTP)12, 1319, 26Hypobetalipoproteinemia (APOB)Familial defective apolipoprotein B (APOB)1411


Description

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.

This pathway was inspired by Chapter 43 of the book of Blau (ISBN 978-3-642-40337-8).

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Bibliography

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  7. Albers JJ, Chen C, Adolphson JL; ''Familial lecithin-cholesterol acyltransferase: identification of heterozygotes with half-normal enzyme activity and mass.''; Hum Genet, 1981 PubMed Europe PMC Scholia
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  11. Baggio G, Manzato E, Gabelli C, Fellin R, Martini S, Enzi GB, Verlato F, Baiocchi MR, Sprecher DL, Kashyap ML; ''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 PubMed Europe PMC Scholia
  12. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ; ''Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.''; N Engl J Med, 2004 PubMed Europe PMC Scholia
  13. Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, McCarthy S, Van Hout CV, Bruse S, Dansky HM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S, Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D, Herman GA, Sheu WHH, Lee IT, Liang KW, Guo X, Rotter JI, Chen YI, Kraus WE, Shah SH, Damrauer S, Small A, Rader DJ, Wulff AB, Nordestgaard BG, Tybjærg-Hansen A, van den Hoek AM, Princen HMG, Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich TM, Yancopoulos GD, Mellis SJ, Gromada J, Baras A; ''Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.''; N Engl J Med, 2017 PubMed Europe PMC Scholia
  14. Carlson LA, Holmquist L; ''Evidence for deficiency of high density lipoprotein lecithin: cholesterol acyltransferase activity (alpha-LCAT) in fish eye disease.''; Acta Med Scand, 1985 PubMed Europe PMC Scholia
  15. Assmann G, Smootz E, Adler K, Capurso A, Oette K; ''The lipoprotein abnormality in Tangier disease: quantitation of A apoproteins.''; J Clin Invest, 1977 PubMed Europe PMC Scholia
  16. Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kuksis A, Kakis G, Lindgren F, Gardiner G; ''Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase.''; Atherosclerosis, 1982 PubMed Europe PMC Scholia
  17. Al-Kateb H, Bähring D, Hoffmann K, Strauch K, Busjahn A, Nürnberg G, Jouma M, Bautz EK, Dresel HA, Luft FC; ''Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.''; Circ Res, 2002 PubMed Europe PMC Scholia
  18. Kathiresan S; ''A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction.''; N Engl J Med, 2008 PubMed Europe PMC Scholia
  19. Ly K, Saavedra YG, Canuel M, Routhier S, Desjardins R, Hamelin J, Mayne J, Lazure C, Seidah NG, Day R; ''Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9.''; J Biol Chem, 2014 PubMed Europe PMC Scholia
  20. Mishra SK, Keyel PA, Edeling MA, Dupin AL, Owen DJ, Traub LM; ''Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein.''; J Biol Chem, 2005 PubMed Europe PMC Scholia
  21. Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjærg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männistö S, Amouyel P, Arveiler D, Ferrieres J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ; ''Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.''; Science, 2016 PubMed Europe PMC Scholia
  22. Hegele RA; ''Plasma lipoproteins: geneticinfluences and clinical implications.''; Nat Rev Genet, 2009 PubMed Europe PMC Scholia
  23. Berger GM; ''An incomplete form of familial lipoprotein lipase deficiency presenting with type I hyperlipoproteinemia.''; Am J Clin Pathol, 1987 PubMed Europe PMC Scholia
  24. Horton JD, Cohen JC, Hobbs HH; ''Molecular biology of PCSK9: its role in LDL metabolism.''; Trends Biochem Sci, 2007 PubMed Europe PMC Scholia
  25. Miller SA, Burnett JR, Leonis MA, McKnight CJ, van Bockxmeer FM, Hooper AJ; ''Novel missense MTTP gene mutations causing abetalipoproteinemia.''; Biochim Biophys Acta, 2014 PubMed Europe PMC Scholia
  26. Blau Nenad, Duran Marinus, Gibson, K, Michael, Dionisi-Vici, Carlo; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; 9783642403361, 2014
  27. Abifadel M, Varret M, Rabès, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C; ''Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.''; Nat Genet, 2003 PubMed Europe PMC Scholia
  28. Haemmerle G, Zimmermann R, Hayn M, Theussl C, Waeg G, Wagner E, Sattler W, Magin TM, Wagner EF, Zechner R; ''Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.''; J Biol Chem, 2002 PubMed Europe PMC Scholia
  29. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG; ''The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.''; J Biol Chem, 2008 PubMed Europe PMC Scholia
  30. Khatun I, Walsh MT, Hussain MM; ''Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia.''; J Lipid Res, 2013 PubMed Europe PMC Scholia
  31. Di Filippo M, Créhalet H, Samson-Bouma ME, Bonnet V, Aggerbeck LP, Rabès JP, Gottrand F, Luc G, Bozon D, Sassolas A; ''Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.''; J Lipid Res, 2012 PubMed Europe PMC Scholia
  32. Griffiths WJ, Abdel-Khalik J, Hearn T, Yutuc E, Morgan AH, Wang Y; ''Current trends in oxysterol research.''; Biochem Soc Trans, 2016 PubMed Europe PMC Scholia
  33. Walsh MT, Iqbal J, Josekutty J, Soh J, Di Leo E, Özaydin E, Gündüz M, Tarugi P, Hussain MM; ''Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function.''; Circ Cardiovasc Genet, 2015 PubMed Europe PMC Scholia
  34. Frohlich J, Hon K, McLeod R; ''Detection of heterozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency.''; Am J Hum Genet, 1982 PubMed Europe PMC Scholia
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  36. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, Grundy SM; ''Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.''; Proc Natl Acad Sci U S A, 1987 PubMed Europe PMC Scholia
  37. Lee J, Hegele RA; ''Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.''; J Inherit Metab Dis, 2014 PubMed Europe PMC Scholia
  38. Eichmann TO, Kumari M, Haas JT, Farese RV Jr, Zimmermann R, Lass A, Zechner R; ''Studies on the substrate and stereo/regioselectivity of adipose triglyceride lipase, hormone-sensitive lipase, and diacylglycerol-O-acyltransferases.''; J Biol Chem, 2012 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
135536view03:01, 23 September 2024EweitzFix gene symbol per Uniprot ID
135535view02:26, 23 September 2024EweitzUse gene symbols
135534view01:54, 23 September 2024EweitzUse gene symbols
128956view22:46, 24 February 2024EweitzUpgrade disease nodes from opaque, bespoke IDs to human-friendly names
128955view22:04, 24 February 2024EweitzFix truncated interaction at bottom of board
128954view21:45, 24 February 2024EweitzFix typo
128953view21:43, 24 February 2024EweitzAdd bespoke disease ID from label to comment, for easy provenance
128952view18:42, 24 February 2024EweitzOntology Term : 'cholesterol-ester transfer protein deficiency' added !
128951view18:36, 24 February 2024EweitzOntology Term : 'abetalipoproteinemia' added !
128950view18:36, 24 February 2024EweitzOntology Term : 'familial apolipoprotein C-II deficiency' added !
128949view18:35, 24 February 2024EweitzOntology Term : 'familial lipoprotein lipase deficiency' added !
128948view15:53, 24 February 2024EweitzSoften disease color
128084view01:16, 24 January 2024EweitzStandardize case
126061view13:55, 31 March 2023DeSlRemoved RHEA prefix
126060view13:54, 31 March 2023DeSlAdded legend
126059view13:53, 31 March 2023DeSlFixed two RHEA IDs
126058view13:52, 31 March 2023DeSlConcerted 2 secondary UniProt IDs to Primary
124275view13:31, 6 October 2022DeSlAdded interpro ID and comment for remnant receptor
124274view13:28, 6 October 2022DeSlConverted arrows to textLabels to graphical lines
119310view13:13, 23 June 2021FinterlyAdded ISBN for book citation
117285view10:56, 20 May 2021DeSlUpdated PW nodes to single border again.
117269view10:44, 20 May 2021DeSlUpdated DataBase for Vit.D PW and Steroid BioSynthesis PW Nodes
117268view10:41, 20 May 2021DeSlTrying to update PW linkouts
117267view10:37, 20 May 2021DeSlUpdated PW Node visualisations
108085view11:52, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
104036view17:48, 25 April 2019IreneHemelModified description
103489view13:52, 6 March 2019DeSlAdded linkout to oxysterols PW.
103448view16:40, 1 March 2019DeSlModified description
103447view16:39, 1 March 2019DeSlModified description
103446view16:28, 1 March 2019DeSlLast updates to diseases
103445view16:19, 1 March 2019DeSlChanged connectivity of PCSK9
103444view15:43, 1 March 2019DeSlReconnected diseases, added MTP protein
103443view15:18, 1 March 2019DeSlUpdated IDs in CM, remnant, HDL2/3, VDLD and IDL.
103442view15:10, 1 March 2019DeSlUpdated Ids for cyclomicrons and remnant.
103441view15:06, 1 March 2019DeSlAdded more IDs.
103440view14:51, 1 March 2019DeSlAdded IDs for VDLD, IDL and LDL.
103439view14:49, 1 March 2019DeSlAdded explanatory text to HDL, LDL and IDL.
103438view14:45, 1 March 2019DeSlUpdated layout
103437view14:42, 1 March 2019DeSlAdded more visualisations from Blau book.
103436view14:27, 1 March 2019DeSlStarted adding drawings from Blau book.
103429view12:39, 28 February 2019DeSlAdded some more info from book on cholesterol pool
103411view16:07, 27 February 2019DeSlAdded more PW linkouts
103408view12:08, 27 February 2019DeSlAdded more PW linkouts
103407view11:53, 27 February 2019DeSlAdded steroid PW links
103406view11:47, 27 February 2019DeSlUpdated LDL transport into cell.
103403view09:51, 27 February 2019DeSlRemoved weird signs in lit. ref; changed long OMIM linkouts to short ones
103399view17:45, 26 February 2019EgonwModified title
103392view19:14, 25 February 2019DeSlConnected diseases to anchors with enzymes, trying to fix test in Jenkins...
103384view11:22, 25 February 2019IngebudeOntology Term : 'altered lipoprotein metabolic pathway' added !
103383view11:22, 25 February 2019IngebudeOntology Term : 'familial combined hyperlipidemia' added !

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(24S)-24,25-epoxycholesterolMetaboliteCHEBI:41633 (ChEBI)
ABCA1GeneProductENSG00000165029 (Ensembl)
ARH LDL receptorProtein
Cyclic fatty acidsMetaboliteCHEBI:59238 (ChEBI)
HL ProteinP11150 (Uniprot-TrEMBL) EC 3.1.1.3
IDLMetaboliteCHEBI:132933 (ChEBI)
LDLMetaboliteCHEBI:39026 (ChEBI)
LPLGeneProductENSG00000175445 (Ensembl)
LactosylceramideMetaboliteCHEBI:10392 (ChEBI)
MethylnorethindroneMetaboliteCHEBI:7630 (ChEBI)
PCSK9GeneProductENSG00000169174 (Ensembl)
Q9Y5X9ProteinQ9Y5X9 (Uniprot-TrEMBL) EC 3.1.1.3
Remnant Protein
Remnant receptorProtein
Rosuvastatin calciumMetaboliteCHEBI:38545 (ChEBI)
SR-B1Protein
VLDLMetaboliteCHEBI:39027 (ChEBI)
lysoPC a C18:2MetaboliteCHEBI:28733 (ChEBI)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
IDLLDLmim-conversionRHEA:12046 (Rhea)
MethylnorethindroneLactosylceramidemim-conversionRHEA:38497 (Rhea)
Q9Y5X9mim-catalysisRHEA:38497 (Rhea)
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