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

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22295, 12, 27, 33, 38168IntestineLiverCellCholesterol pool4Cholesterol is the precursor for steroid hormones.Endocytosis43.2.1Chyclomicron17, 36HL MTPCETPLPLLDL-receptorABCA1Cyclic fatty acidsNuclear hormone receptors(involved in sterol metabolism)Steroid Biosynthesis(general overview)Annexin A2LDLRPCSK9LDLRAP1CholesterolLPLVit. D pathwayOxysterolsHLLCATSR-B1Remnant receptorC-II25247143.2.22943.5.1243.5.219, 2343.6.22621943.3.243.1.11843.1.23343.3.120, 3143.4.143.4.430, 3243.4.32835, 3743.4.21143.3.31543.1.443.2.33413, 3443.2.143.2.217, 3643.1.3146Cholesterol25CholesterolCholesterolClassical steroidogenesis(including diseases)Alternative steroidogenesis(including diseases)Bile AcidsB48EVLDLB100RemnantB48EHDL3A-IA-IIHDL2A-IIDLB100LDLB100C-IIEE43.3.243.1.57, 1016MTP165, 12, 27, 33, 38


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. More details on the composition of the various lipoproteins in this pathway are visualised in [1].

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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  13. Kathiresan S; ''A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction.''; N Engl J Med, 2008 PubMed
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  27. 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
  28. 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
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  34. 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
  35. Frohlich J, Hon K, McLeod R; ''Detection of heterozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency.''; Am J Hum Genet, 1982 PubMed
  36. Lee J, Hegele RA; ''Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.''; J Inherit Metab Dis, 2014 PubMed
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History

View all...
CompareRevisionActionTimeUserComment
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 !
103382view11:19, 25 February 2019IngebudeChanged identifiers of 2 geneproducts
103378view09:02, 25 February 2019Mkutmonfixed special characters in literature references
103375view18:36, 24 February 2019IngebudeChanged identifiers HDL
103266view09:03, 20 February 2019IngebudeChanged anchor
103265view08:51, 20 February 2019IngebudeSwitched around arrows
103252view14:42, 18 February 2019Ingebude
103245view10:17, 18 February 2019Ingebude
103243view10:10, 18 February 2019IngebudeAdded identifiers AHR LDL receptor and PCSK9 inhbitor
103233view09:05, 18 February 2019IngebudeChanged metabolites to geneproducts
103227view08:39, 18 February 2019IngebudeOntology Term : 'familial combined hyperlipidemia pathway' added !
103225view08:37, 18 February 2019IngebudeOntology Term : 'autosomal recessive hypercholesterolemia' added !
103224view08:37, 18 February 2019IngebudeOntology Term : 'Tangier disease' added !
103223view08:35, 18 February 2019IngebudeOntology Term : 'hypobetalipoproteinemia' added !
103222view08:33, 18 February 2019IngebudeChanged ref book by Blau
103219view08:21, 18 February 2019IngebudeModified description
103218view08:21, 18 February 2019IngebudeAdded missing disease
103212view13:53, 17 February 2019DeSlGrouped diseases, connected arrows again to group, changed arrow to graphical lines for diseases.
103211view19:03, 16 February 2019IngebudeModified description
103199view15:43, 15 February 2019IngebudeOntology Term : 'triacylglycerol metabolic pathway' added !
103198view15:43, 15 February 2019IngebudeOntology Term : 'lipoprotein metabolic pathway' added !
103185view15:14, 15 February 2019LobkeMfinetuned layout
103176view14:50, 15 February 2019IngebudeAdded all litref of diseases
103163view14:24, 15 February 2019IngebudeAdded litref of some diseases
103158view13:59, 15 February 2019IngebudeChecked litref
103156view13:46, 15 February 2019IngebudeAdded Rhea
103144view09:23, 15 February 2019IngebudeChanged colour diseases and changed proteins to metabolites

External references

DataNodes

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NameTypeDatabase referenceComment
A-IIProteinP02652 (Uniprot-TrEMBL) AKA Apolipoprotein A-II
A-IProteinP02647 (Uniprot-TrEMBL) AKA Apo A-I; activator of lecithin-cholesterol acyl transferase (LCAT).
ABCA1GeneProductENSG00000165029 (Ensembl)
Alternative steroidogenesis (including diseases)PathwayWP4524 (WikiPathways)
Annexin A2ProteinH0YKN4 (Uniprot-TrEMBL)
B100ProteinP04114 (Uniprot-TrEMBL)
  • "Apoprotein B100 (ApoB-100) is embedded in the outer phospholipid layer of LDL particles." [https://en.wikipedia.org/wiki/LDL_receptor]
  • Synthesized in liver.
B48ProteinA8MUN2 (Uniprot-TrEMBL)
  • "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.
Bile AcidsPathwayWP4389 (WikiPathways)
C-IIProteinP02655 (Uniprot-TrEMBL) AKA Apolipoprotein C2; cofactor for lipoprotein lipase (LPL) enzyme.
CETPGeneProductENSG00000087237 (Ensembl)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
Classical steroidogenesis (including diseases)PathwayWP4523 (WikiPathways)
Cyclic fatty acidsMetaboliteCHEBI:59238 (ChEBI)
EProteinP02649 (Uniprot-TrEMBL) AKA APo E, a ligand for receptor mediated endocytosis.
HL GeneProductP11150 (Uniprot-TrEMBL) EC 3.1.1.3
HLGeneProductQ9Y5X9 (Uniprot-TrEMBL) EC 3.1.1.3 aka LIPC
IDLMetaboliteCHEBI:132933 (ChEBI) Itermediate-density lipoprotein (IDL), physiologically a short lived species, containd around equimolar amounts of cholesterol and Triglycerides (TG).
LCATGeneProductENSG00000213398 (Ensembl) AKA Lecithin-cholesterol acyl transferase
LDL-receptorProteinP01130 (Uniprot-TrEMBL)
LDLMetaboliteCHEBI:39026 (ChEBI) Low-density lipoprotein (LDL) is one of the two main cholesterol carrying lipoproteins, which are spheroidal macromolecular complexes responsible for transporting lipids through plasma.
LDLRAP1ProteinQ5SW96 (Uniprot-TrEMBL)
  • 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]
LDLRProteinENSG00000130164 (Ensembl)
LPLGeneProductENSG00000175445 (Ensembl)
MTPGeneProductP55157 (Uniprot-TrEMBL) "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]
Nuclear hormone receptors (involved in sterol metabolism)PathwayWP299 (WikiPathways)
OxysterolsPathwayWP4545 (WikiPathways)
  • "Oxysterols are oxygenated derivatives of cholesterol or its sterol precursors, e.g. 7-dehydrocholesterol (7-DHC) or desmosterol" [ PubMed 27068984].
  • See https://www.wikipathways.org/index.php/Pathway:WP4346 for mouse version (Human will be created at some point).
PCSK9GeneProductENSG00000169174 (Ensembl)
Remnant receptorProtein
SR-B1ProteinQ8WTV0 (Uniprot-TrEMBL) AKA SCARB1; Receptor for HDL, mediating selective uptake of cholesteryl ether and HDL-dependent cholesterol efflux.
Steroid Biosynthesis (general overview)PathwayWP496 (WikiPathways)
VLDLMetaboliteCHEBI:39027 (ChEBI) 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.
Vit. D pathwayPathwayWP1531 (WikiPathways)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
HLmim-catalysisRHEA:38497 (Rhea)
mim-conversionRHEA:12046 (Rhea)
mim-conversionRHEA:38497 (Rhea)
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