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

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2018LiverIntestineCholesterol poolCellAbetalipoproteinemia (MTP)1, 12ARH LDL receptorLactosylceramideIDLRosuvastatin calciumRemnant receptorCyclic fatty acidsMethylnorethindroneHL ABCA1(24S)-24,25-epoxycholesterolLPLlysoPC a C18:2PCSK9Q9Y5X9LDLSR-B1RemnantVLDLLPLHypobetalipoproteinemia (APOB)4Lipoprotein lipase deficiency (LPL)3, 6Apolipoprotein C2 deficiency (APOC2)Dysbetalipoproteinemia (APOE)15214Hepatic lipase deficiency (LIPC)7Familial hypercholesterolemia heterozygous (LDLR)5Familial hypercholesterolemia homozygous (LDLR)Autosomal recessive hypercholesterolemia (ARH)5Cholesteryl ester transfer protein deficiency (CETP)10Tangier disease (ABCA1)8, 11Familial LCAT deficiency (partial)13, 2126Familial LCAT deficiency (complete)16, 24Apolipoprotein A-1 deficiency (APOA1)19Scavenger receptor B1 deficiency (SCARB1)22Autosomal dominant hypercholesterolemiaPCSK9 deficiency with low LDL17Abetalipoproteinemia (MTP)17, 231, 12Hypobetalipoproteinemia (APOB)Familial defective apolipoprotein B (APOB)925


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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  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
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  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
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  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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  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 calciumGeneProductCHEBI:38545 (ChEBI)
SR-B1Protein
VLDLMetaboliteCHEBI:39027 (ChEBI)
lysoPC a C18:2GeneProductCHEBI:28733 (ChEBI)

Annotated Interactions

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