Oxysterols derived from cholesterol (Homo sapiens)

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510, 1822222216161633, 4NPC1CD4+ Th17 cellsSLOSHSDB19, 2867, 12ROR-γt IL-17ADHCR77-beta, (25R)26-diHCD8D7IhistamineLXR-alphaCyp7B124S-diHCCholesterolEstrogen receptor alphaEBI2DDA27225,6-alpha-EpoxycholesterolCholestane-3-beta,5-alpha, 6-beta-triol7-beta-HC7-alpha-HC25-HC7-alpha,25-diHC2, 15, 17, 2610, 18(25R)26-HC7-alpha, (25R)26-diHC222223, 29-3123, 251, 9, 12, 13, 2311, 20, 24Cyp27A1Cyp27A114, 21Cyp7A114, 21Cyp27A1Cyp7B114, 21CH25HCyp46A1ChEH22IL-17BIL-17CIL-17DIL-17EIL-17F1616Estrogen receptor betaLXR-betaCTX19SPG519, 28NP Type B8NP type A8


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.

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Bibliography

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  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Toll A, Wikvall K, Sudjana-Sugiaman E, Kondo KH, Björkhem I; ''7 alpha hydroxylation of 25-hydroxycholesterol in liver microsomes. Evidence that the enzyme involved is different from cholesterol 7 alpha-hydroxylase.''; Eur J Biochem, 1994 PubMed Europe PMC
  10. 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
  11. Jelinek DF, Andersson S, Slaughter CA, Russell DW; ''Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.''; J Biol Chem, 1990 PubMed Europe PMC
  12. Yantsevich AV, Dichenko YV, Mackenzie F, Mukha DV, Baranovsky AV, Gilep AA, Usanov SA, Strushkevich NV; ''Human steroid and oxysterol 7α-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants.''; FEBS J, 2014 PubMed Europe PMC
  13. 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
  14. Pikuleva IA, Babiker A, Waterman MR, Björkhem I; ''Activities of recombinant human cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways.''; J Biol Chem, 1998 PubMed Europe PMC
  15. 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
  16. 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
  17. 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
  18. 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
  19. Clayton PT; ''Disorders of bile acid synthesis.''; J Inherit Metab Dis, 2011 PubMed Europe PMC
  20. Noshiro M, Okuda K; ''Molecular cloning and sequence analysis of cDNA encoding human cholesterol 7 alpha-hydroxylase.''; FEBS Lett, 1990 PubMed Europe PMC
  21. 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
  22. 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
  23. Russell DW; ''The enzymes, regulation, and genetics of bile acid synthesis.''; Annu Rev Biochem, 2003 PubMed Europe PMC
  24. Norlin M, Toll A, Björkhem I, Wikvall K; ''24-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase (CYP7A).''; J Lipid Res, 2000 PubMed Europe PMC
  25. 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
  26. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG; ''''; , PubMed Europe PMC
  27. 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
  28. Shackleton CH; ''Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis.''; Lipids, 2012 PubMed Europe PMC
  29. 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
  30. Lund EG, Guileyardo JM, Russell DW; ''cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.''; Proc Natl Acad Sci U S A, 1999 PubMed Europe PMC
  31. Mast N, White MA, Bjorkhem I, Johnson EF, Stout CD, Pikuleva IA; ''Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
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].
5,6-alpha-EpoxycholesterolMetaboliteQ27121609 (Wikidata) AKA 5,6α-epoxycholesterol
7-alpha, (25R)26-diHCMetaboliteQ28487682 (Wikidata) AKA 7α,26-dihydroxycholesterol (7α,26-diHC).
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)
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)
Cyp46A1ProteinQ9Y6A2 (Uniprot-TrEMBL) Responsible for cholesterol homeostasis in brain.
Cyp7A1ProteinP22680 (Uniprot-TrEMBL) cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.
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.
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)
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

SourceTargetTypeDatabase referenceComment
25-HC7-alpha,25-diHCmim-conversion24309 (Rhea)
Cholesterol24S-diHCmim-conversion22717 (Rhea)
Cholesterol25-HCmim-conversion21105 (Rhea)
Cholesterol7-alpha-HCmim-conversion21813 (Rhea)
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