Oxysterols derived from cholesterol (Homo sapiens)

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7α-Hydroxylase pathway:neutral/classical pathwayof bile acid biosynthesis415, 302726273030302621273011, 22262112, 2411HSDBNPC1SLOSCD4+ Th17 cells71, 514, 207-beta, (25R)26-diHC24S-diHCDDAEstrogen receptor alphaCholesterol3β,7α-diHCAROR-γt DHCR77α,25-diHCOhistamine7α,25-diHCCyp3A4IL-17AHSD3B7EBI2PXRCyp7B17α(25S)26-diHCLXR-alphaEBI2D8D7I7α−HCOHSD3B730275,6-alpha-Epoxycholesterol3015309Cholestane-3-beta,5-alpha, 6-beta-triol7-beta-HC7-alpha-HC25-HC6, 13, 18, 347-alpha,25-diHC(25R)26-HC12, 24307α,26-diHC272719, 31-333, 322, 16, 20, 29, 323017, 23, 25, 30Cyp27A18, 28, 30Cyp27A18, 28Cyp7A1Cyp27A130Cyp7B18, 28, 30CH25HCyp46A1ChEH27IL-17BIL-17CIL-17DIL-17EIL-17F26Estrogen receptor beta26LXR-betaCTX1SPG51, 5NP Type BNP type A10107α−HCO30307-alpha-HC3015, 307α(25S)26-diHCO30


Description

The Oxysterol group of compounds are oxygenated derivatives of cholesterol or its sterol precursors, e.g. 7-dehydrocholesterol (7-DHC) or desmosterol. There are three mechanisms leading to the formation of oxysterols:

1. Enzymatically (first steps of sterol metabolism, being intermediates for the formation of steroid hormones, bile acids and 1,25-dihydroxyvitamin D3). 2. Non-enzymatically by encountering reactive oxygen species (ROS), providing a second pool of metabolites (this pool also includes oxidized cholesterol molecules taken in from diet). 3. Generation by the gut microflora and uptake through the enterohepatic circulation.


Previously oxysterols where though to be inactive metabolic intermediates, however recent findings have established that these metabolites are involved in cholesterol homoeostasis, can be ligands to nuclear and G protein-coupled receptors and biomarkers of diseases (for example Niemann-Pick disease).

This pathway drawing was inspired by Figure 3 of the review article by Griffiths et al. (2016) [1], and has been extended with immune system, receptor agonists, steroidal alkaloid and biomarker information from the same paper. We are currently updating this pathways with Figure 1 from Griffiths et al (2020) [2].

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Bibliography

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  2. Wu Z, Martin KO, Javitt NB, Chiang JY; ''Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene CYP7B1.''; J Lipid Res, 1999 PubMed Europe PMC Scholia
  3. Lund EG, Kerr TA, Sakai J, Li WP, Russell DW; ''cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism.''; J Biol Chem, 1998 PubMed Europe PMC Scholia
  4. 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
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  6. Bauman DR, Bitmansour AD, McDonald JG, Thompson BM, Liang G, Russell DW; ''25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production.''; Proc Natl Acad Sci U S A, 2009 PubMed Europe PMC Scholia
  7. Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, Olzeski D, Sidhu R, Dietzen DJ, Fu R, Wassif CA, Yanjanin NM, Marso SP, House J, Vite C, Schaffer JE, Ory DS; ''Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease.''; Sci Transl Med, 2010 PubMed Europe PMC Scholia
  8. Bodin K, Andersson U, Rystedt E, Ellis E, Norlin M, Pikuleva I, Eggertsen G, Björkhem I, Diczfalusy U; ''Metabolism of 4 beta -hydroxycholesterol in humans.''; J Biol Chem, 2002 PubMed Europe PMC Scholia
  9. Villey I, de Chasseval R, de Villartay JP; ''RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma / TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter.''; Eur J Immunol, 1999 PubMed Europe PMC Scholia
  10. Klinke G, Rohrbach M, Giugliani R, Burda P, Baumgartner MR, Tran C, Gautschi M, Mathis D, Hersberger M; ''LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.''; Clin Biochem, 2015 PubMed Europe PMC Scholia
  11. Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP; ''27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.''; Science, 2013 PubMed Europe PMC Scholia
  12. Liu C, Yang XV, Wu J, Kuei C, Mani NS, Zhang L, Yu J, Sutton SW, Qin N, Banie H, Karlsson L, Sun S, Lovenberg TW; ''Oxysterols direct B-cell migration through EBI2.''; Nature, 2011 PubMed Europe PMC Scholia
  13. Blanc M, Hsieh WY, Robertson KA, Kropp KA, Forster T, Shui G, Lacaze P, Watterson S, Griffiths SJ, Spann NJ, Meljon A, Talbot S, Krishnan K, Covey DF, Wenk MR, Craigon M, Ruzsics Z, Haas J, Angulo A, Griffiths WJ, Glass CK, Wang Y, Ghazal P; ''The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response.''; Immunity, 2013 PubMed Europe PMC Scholia
  14. Cheng JB, Jacquemin E, Gerhardt M, Nazer H, Cresteil D, Heubi JE, Setchell KD, Russell DW; ''Molecular genetics of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease.''; J Clin Endocrinol Metab, 2003 PubMed Europe PMC Scholia
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  21. Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, Forman BM; ''Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance.''; Proc Natl Acad Sci U S A, 2003 PubMed Europe PMC Scholia
  22. Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, Mangelsdorf DJ; ''27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen.''; Nat Med, 2007 PubMed Europe PMC Scholia
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  24. Hannedouche S, Zhang J, Yi T, Shen W, Nguyen D, Pereira JP, Guerini D, Baumgarten BU, Roggo S, Wen B, Knochenmuss R, Noël S, Gessier F, Kelly LM, Vanek M, Laurent S, Preuss I, Miault C, Christen I, Karuna R, Li W, Koo DI, Suply T, Schmedt C, Peters EC, Falchetto R, Katopodis A, Spanka C, Roy MO, Detheux M, Chen YA, Schultz PG, Cho CY, Seuwen K, Cyster JG, Sailer AW; ''Oxysterols direct immune cell migration via EBI2.''; Nature, 2011 PubMed Europe PMC Scholia
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  26. Soroosh P, Wu J, Xue X, Song J, Sutton SW, Sablad M, Yu J, Nelen MI, Liu X, Castro G, Luna R, Crawford S, Banie H, Dandridge RA, Deng X, Bittner A, Kuei C, Tootoonchi M, Rozenkrants N, Herman K, Gao J, Yang XV, Sachen K, Ngo K, Fung-Leung WP, Nguyen S, de Leon-Tabaldo A, Blevitt J, Zhang Y, Cummings MD, Rao T, Mani NS, Liu C, McKinnon M, Milla ME, Fourie AM, Sun S; ''Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation.''; Proc Natl Acad Sci U S A, 2014 PubMed Europe PMC Scholia
  27. de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, Lacroix-Triki M, Filleron T, Pont F, Saati TA, Morisseau C, Hammock BD, Silvente-Poirot S, Poirot M; ''Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.''; Nat Commun, 2013 PubMed Europe PMC Scholia
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  29. Li-Hawkins J, Lund EG, Bronson AD, Russell DW; ''Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24-hydroxycholesterol.''; J Biol Chem, 2000 PubMed Europe PMC Scholia
  30. Griffiths WJ, Wang Y; ''Oxysterols as lipid mediators: Their biosynthetic genes, enzymes and metabolites.''; Prostaglandins Other Lipid Mediat, 2020 PubMed Europe PMC Scholia
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  32. Russell DW; ''The enzymes, regulation, and genetics of bile acid synthesis.''; Annu Rev Biochem, 2003 PubMed Europe PMC Scholia
  33. Mast N, Norcross R, Andersson U, Shou M, Nakayama K, Bjorkhem I, Pikuleva IA; ''Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain.''; Biochemistry, 2003 PubMed Europe PMC Scholia
  34. Diczfalusy U, Olofsson KE, Carlsson AM, Gong M, Golenbock DT, Rooyackers O, Fläring U, Björkbacka H; ''Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide.''; J Lipid Res, 2009 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
111450view18:32, 10 August 2020EgonwRemoved the RHEA: part
111446view13:27, 10 August 2020DeSlAdded Rhea ID and literature for Cyp27A1 reaction.
111445view13:14, 10 August 2020DeSlAdded up to 7α(25S)26-diHCO.
111444view13:07, 10 August 2020DeSlAdded EBI2 stimulation
111443view11:23, 10 August 2020DeSlAdded untill 7α,25-diHCO
111442view09:36, 10 August 2020DeSlAdded PXR ligand step
111441view09:32, 10 August 2020DeSlAdded 7α−HCO step.
111440view08:42, 10 August 2020DeSlModified description
111435view08:35, 10 August 2020DeSlAdded 3β,7α-diHCA step.
110346view07:42, 7 May 2020FehrhartOntology Term : 'cerebrotendinous xanthomatosis' added !
105674view19:22, 12 August 2019EgonwReplaced a gene ID with the matching UniProt ID.
105673view18:50, 12 August 2019EgonwCompleted a few UniProt identifiers.
104248view18:49, 11 May 2019EgonwRemoved the RHEA: prefix from the identifier.
103580view12:15, 18 March 2019DeSlModified description
103488view13:34, 6 March 2019DeSlOntology Term : 'cerebrotendinous xanthomatosis pathway' added !
103487view13:34, 6 March 2019DeSlOntology Term : 'Niemann-Pick disease type C1' added !
103486view13:34, 6 March 2019DeSlOntology Term : 'Niemann-Pick disease type B' added !
103485view13:34, 6 March 2019DeSlOntology Term : 'Niemann-Pick disease' added !
103484view13:34, 6 March 2019DeSlOntology Term : 'Niemann-Pick disease type A' added !
103483view13:34, 6 March 2019DeSlOntology Term : 'sterol regulatory element-binding protein signaling pathway' added !
103482view13:33, 6 March 2019DeSlOntology Term : 'cholesterol metabolic pathway' added !
103481view13:32, 6 March 2019DeSlModified description
103480view13:22, 6 March 2019DeSlAdded more IDs for metabolites (and Cyp46A1).
103479view13:16, 6 March 2019DeSlAdded more details from lit. ref.
103478view12:44, 6 March 2019DeSlAdded "subunits" of ChEH
103477view12:35, 6 March 2019DeSlAdded more IDs and Lit. ref info.
103476view12:02, 6 March 2019DeSlAdded more IDs
103475view10:59, 6 March 2019DeSlNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
(25R)26-HCMetaboliteQ15634124 (Wikidata) "AKA (25R)26-hydroxycholesterol; Named with systematic nomenclature, where hydroxylation at the terminal side chain of cholesterol is on C-26 leading to 26-hydroxycholesterol (26-HC) which may have 25R or 25S stereochemistry [26]. Unless stated otherwise 25R stereochemistry is assumed. In much of the literature (25R)26-HC is referred to 27-hydroxycholesterol (27-HC), presumably the 25R isomer."
24S-diHCMetaboliteQ27071873 (Wikidata) AKA (24S)-hydroxycholesterol
25-HCMetaboliteQ27071875 (Wikidata)
  • AKA 25-Hydroxycholesterol
  • Produced by macrophages [PMID: 19805370, 19502589, 23273843], in vivo [PMID: 25104388].
3β,7α-diHCAMetaboliteQ27154974 (Wikidata) Aka 3β,7α-dihydroxycholest-5-en-(25R)26-oic acid
5,6-alpha-EpoxycholesterolMetaboliteQ27121609 (Wikidata) AKA 5,6α-epoxycholesterol
7-alpha,25-diHCMetaboliteQ27074018 (Wikidata)
  • AKA 7α,25-Dihydroxycholesterol
  • Involved in immune response (agonist of G-protein-coupled receptor EBI2 (AKA GPR183)) [PMID: 21796212, 21796211].
7-alpha-HCMetaboliteQ155744 (Wikidata) AKA 7α-hydroxycholesterol (7α-HC)
7-beta, (25R)26-diHCMetaboliteQ27074030 (Wikidata) AKA 7β,26-dihydroxycholesterol (7β,26-diHC).
7-beta-HCMetaboliteQ27074031 (Wikidata) AKA 7β-hydroxycholesterol (7β-HC)
7α(25S)26-diHCMetaboliteaka 7α,(25S)26-dihydroxycholesterol
7α(25S)26-diHCOMetaboliteaka 7α,(25S)26-dihydroxycholest-4-en-3-one
7α,25-diHCMetaboliteCHEBI:37623 (ChEBI)
  • aka 7α,25-dihydroxycholesterol
  • "the most potent EBI2 agonist 7α,25-dihydroxycholesterol (7α,25-diHC))" [PMID:31698146]
7α,25-diHCOMetaboliteCHEBI:81013 (ChEBI) aka 7α,25-dihydroxycholest-4-en-3-one
7α,26-diHCMetaboliteQ28487682 (Wikidata) AKA 7α,26-dihydroxycholesterol; 7-alpha, (25R)26-diHC
7α−HCOMetaboliteCHEBI:17899 (ChEBI)
  • aka 7α-hydroxycholest-4-en-3-one
  • "7α−HCO is a ligand to the pregnane X receptor (PXR), a member of the nuclear receptor superfamily" [PMID:31698146]
CH25HProteinO95992 (Uniprot-TrEMBL) AKA cholesterol 25-hydroxylase
ChEHProteinP34913 (Uniprot-TrEMBL)
  • AKA cholesterol epoxide hydrolase (ChEH); EC: 3.3.2.11
  • "ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)"
Cholestane-3-beta, 5-alpha, 6-beta-triolMetaboliteQ27103493 (Wikidata)
  • AKA cholestane-3β,5α,6β-triol
  • "Biomarker for NPC1; elevated levels of cholestane-3β,5α,6β-triol in plasma from NPC1 patients." [PMID: 21048217].
CholesterolMetaboliteQ43656 (Wikidata)
Cyp27A1ProteinQ02318 (Uniprot-TrEMBL)
Cyp3A4ProteinP08684 (Uniprot-TrEMBL) Reaction also occurs in mouse: CYP3A11
Cyp46A1ProteinQ9Y6A2 (Uniprot-TrEMBL) Responsible for cholesterol homeostasis in brain.
Cyp7A1ProteinP22680 (Uniprot-TrEMBL)
  • cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.
  • "the transcript of which is almost exclusively expressed in liver" [PMID:31698146]
Cyp7B1ProteinO75881 (Uniprot-TrEMBL)
D8D7IProtein"ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)"
DDAMetaboliteQ61983671 (Wikidata) AKA Dendrogenin A
DHCR7ProteinQ9UBM7 (Uniprot-TrEMBL) "ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)"
EBI2ProteinP32249 (Uniprot-TrEMBL) AKA G protein-coupled receptor EBI2 (GPR183)
Estrogen receptor alphaProteinP03372 (Uniprot-TrEMBL) Expressed in vascular cells.
Estrogen receptor betaProteinQ92731 (Uniprot-TrEMBL) Expressed in vascular cells.
HSD3B7ProteinQ9H2F3 (Uniprot-TrEMBL)
IL-17AProteinQ16552 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
IL-17BProteinQ9UHF5 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
IL-17CProteinQ9P0M4 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
IL-17DProteinQ8TAD2 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
IL-17EProteinQ9H293 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
IL-17FProteinQ96PD4 (Uniprot-TrEMBL) "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323]
LXR-alphaProteinP13133 (Uniprot-TrEMBL)
LXR-betaProteinP55055 (Uniprot-TrEMBL)
PXRProteinO75469 (Uniprot-TrEMBL)
ROR-γt ProteinF1D8P6 (Uniprot-TrEMBL)
  • AKA RAR-related orphan receptor gamma (RORγt); consists of 2 isoforms: RORγ and RORγt. This nuclear receptor is required for generating IL-17-producing CD4(+) Th17 T cells.
  • "RORγt (also known as RORγ2) – produced from an mRNA identical to that of RORγ, except that the two 5'-most exons are replaced by an alternative exon, located downstream in the gene. This causes a different, shorter N-terminus." [https://en.wikipedia.org/wiki/RAR-related_orphan_receptor_gamma]
histamineMetaboliteQ61233 (Wikidata)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
25-HC7-alpha,25-diHCmim-conversion24309 (Rhea)
7-alpha-HC7α−HCOmim-conversion11897 (Rhea) oxidation
7α,25-diHC7α,25-diHCOmim-conversion47157 (Rhea)
Cholesterol(25R)26-HCmim-conversion46401 (Rhea)
Cholesterol24S-diHCmim-conversion22717 (Rhea)
Cholesterol25-HCmim-conversion21105 (Rhea)
Cholesterol7-alpha-HCmim-conversion21813 (Rhea) 7α-hydroxylation
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