Oxysterols derived from cholesterol (WP4545)

Homo sapiens

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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), see https://www.wikipathways.org/instance/WP5064, and 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, and has been extended with immune system, receptor agonists, steroidal alkaloid and biomarker information from the same paper. This pathway has been updated with Figure 1 from Griffiths et al. 2020 (green areas), Figure 2 (yellow area) and Figure 3 (blue area).

Authors

Denise Slenter , Egon Willighagen , Friederike Ehrhart , Conroy lipids , Robert Andrews , William J Griffiths , Alex Pico , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Lipids and LIPID MAPS Rare Diseases

Annotations

Disease Ontology

cerebrotendinous xanthomatosis alpha-methylacyl-CoA racemase deficiency Niemann-Pick disease type B Niemann-Pick disease congenital bile acid synthesis defect 6 Niemann-Pick disease type C1 D-bifunctional protein deficiency Niemann-Pick disease type A congenital bile acid synthesis defect

Cell Type Ontology

CD4-positive helper T cell

Pathway Ontology

familial hypercholanemia pathway cerebrotendinous xanthomatosis pathway classic metabolic pathway sterol regulatory element-binding protein signaling pathway cholesterol metabolic pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
3beta-hydroxy-7beta-N-acetylglucosaminylchol-5-en-24-oyltaurine Metabolite lipidmaps:LMST04010472
BA-delta5-3beta,7beta-diol 7betaGlcNAc Metabolite lipidmaps:LMST04010467
3beta-hydroxy-7beta-N-acetylglucosaminylchol-5-en-24-oylglycine Metabolite lipidmaps:LMST04010471
5,6-epoxycholesterolsulfate Metabolite lipidmaps:LMST05020067
3beta-Sulfooxy-7beta-N-acetylglucosaminylchol-5-en-24-oic acid Metabolite lipidmaps:LMST04010468
7α,24R-Dihydroxy-3-oxocholest-4-en-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030256
7α,12α−Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030114 aka 7alpha-hydroxycholest-4-en-3-one
7β,(25R)26-Dihydroxycholesterol Metabolite lipidmaps:LMST04030178 AKA 7β,26-dihydroxycholesterol (7β,26-diHC).
7α-Hydroxy-3-oxocholest-4,24(E)-dien-26-oyl-CoA Metabolite lipidmaps:LMST04030258
histamine Metabolite wikidata:Q61233
7α-Hydroxy-3-oxochol-4-en-24-oyl-CoA Metabolite lipidmaps:LMST04010462
7α(25S)26-Dihydroxycholesterol Metabolite lipidmaps:LMST01010466 aka 7α,(25S)26-dihydroxycholesterol
3α,7α,12α−Trihydroxy-5β-cholestan-(25R)26-oic acid Metabolite lipidmaps:LMST04030151 AKA (25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid
7α-Hydroxy-3-oxochol-4-en-24-oyl-taurine Metabolite lipidmaps:LMST05040022
Dendrogenin A Metabolite lipidmaps:LMST05050025 AKA Dendrogenin A
5β-Cholestane-3α,7α,12α,(25R)26-tetrol Metabolite lipidmaps:LMST04030160 aka (25R)-5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol
Cholesterol Metabolite lipidmaps:LMST01010001
7α,24S-Dihydroxy-3-oxocholest-4-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030247
7α,25-Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030107 aka 7α,25-dihydroxycholest-4-en-3-one
7α-Hydroxy-3-oxocholest-4-en-(25S)26-oyl-CoA Metabolite lipidmaps:LMST04030253 aka 7α-Hydroxy-3-oxocholest-4-en-(25S)26-oyl-CoA
24S-hydroxycholesterol Metabolite lipidmaps:LMST01010019 AKA 24S-hydroxycholesterol
Can corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719]
7α-Hydroxy-3-oxocholest-4-en-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030252 aka 7α-Hydroxy-3-oxocholest-4-en-(25R)26-oyl-CoA
7α,24S-Dihydroxy-3-oxocholest-4-en-(25R)26-oyl CoA Metabolite lipidmaps:LMST04030251
7α,12α,(25R)26-Trihydroxy-5β-cholestan-3-one Metabolite lipidmaps:LMST04030246 aka 7α,12α,(25R)26-TriHydroxy-5β-cholestan-3-one
3β,7α-Dihydroxycholest-5-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030241 Aka 3β,7α-dihydroxycholest-5-en-(25R)26-oic acid
7α,25-Dihydroxycholesterol Metabolite lipidmaps:LMST04030166 aka 7α,25-dihydroxycholesterol
'the most potent EBI2 agonist 7α,25-dihydroxycholesterol (7α,25-diHC))' [PMID:31698146]
7α-Hydroxy-3-oxochol-4-en-24-oic acid Metabolite lipidmaps:LMST04010239
7α-Hydroxy-3-oxochol-4-en-24-oyl-glycine Metabolite lipidmaps:LMST05030020
7α−Hydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030123 aka 7α-hydroxycholest-4-en-3-one
7α-Hydroxy-3,24-bisoxocholest-4-en-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030254
5α,6α-Epoxycholesterol Metabolite lipidmaps:LMST01010011 AKA 5,6α-epoxycholesterol
Cholestane-3β,5α,6β-triol Metabolite lipidmaps:LMST01010510 AKA cholestane-3β,5α,6β-triol
'Biomarker for NPC1; elevated levels of cholestane-3β,5α,6β-triol in plasma from NPC1 patients.' [PMID: 21048217].
7β-Hydroxycholesterol Metabolite lipidmaps:LMST01010047 AKA 7β-hydroxycholesterol (7β-HC)
7α-Hydroxycholesterol Metabolite lipidmaps:LMST01010013 AKA 7α-hydroxycholesterol (7α-HC)
25-Hydroxycholesterol Metabolite lipidmaps:LMST01010018 AKA 25-Hydroxycholesterol
Produced by macrophages [PMID: 19805370, 19502589, 23273843], in vivo [PMID: 25104388].
7α,25-Dihydroxycholesterol Metabolite lipidmaps:LMST04030166 AKA 7α,25-Dihydroxycholesterol
Involved in immune response (agonist of G-protein-coupled receptor EBI2 (AKA GPR183)) [PMID: 21796212, 21796211].
(25R)26-Hydroxycholesterol Metabolite lipidmaps:LMST01010088 '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.' [PMID:22366074]
'26-HC, 25R-stereochemistry is assumed unless indicated otherwise, also called 27-hydroxycholesterol' [PMID:31698146]
7α,(25R)26-Dihydroxycholesterol Metabolite lipidmaps:LMST01010462 AKA 7α,26-dihydroxycholesterol; 7-alpha, (25R)26-diHC
7α−Hydroxycholest-4-en-3-one Metabolite chebi:17899 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]
7α(25S)26-Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST01010465 aka 7α,(25S)26-dihydroxycholest-4-en-3-one
7α,12α−Dihydroxy-5β-cholestan-3-one Metabolite lipidmaps:LMST04030113 aka 7alpha,12alpha-dihydroxy-5beta-cholestan-3-one
5β-Cholestane-3α,7α,12α−triol Metabolite lipidmaps:LMST04030035 aka 5beta-cholestane-3alpha,7alpha,12alpha-triol ; trihydroxycoprostane
3β-Hydroxycholest-5-en-(25R)-26-oicacid Metabolite lipidmaps:LMST04030072 'AKA (25R)-3beta-hydroxycholest-5-en-26-oic acid; 3β-HC-5-en-(25R)26-oic acid
'Pathway starting from this metabolite to 3β,7alpha-HCA is considered the acidic or alternative PW of bile acid biosynthesis' [PMID:31698146,12543708]
7α,(25R)26−Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST01010463 aka (25R)-7alpha,26-dihydroxycholest-4-en-3-one
7α-Hydroxy-3-oxocholest-4-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030242 aka 7-Hydroxy-3-oxocholest-4-en-(25R)26-oic acid
7α, 12α,(25R)26−Trihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST01010464 aka 7alpha,12alpha,(25R)26-trihydroxycholest-4-en-3-one
7α,12α-Dihydroxy-3-oxocholest-4-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030243 aka 7-alpha,12-alpha-diHydroxy-3-oxocholest-4-en-(25R)26-oic acid (not available in Wikidata)
7α,12α-Dihydroxy-3-oxo-5β-cholestan-(25R)26-oic acid Metabolite lipidmaps:LMST04030245 aka 7α,12α-diHydroxy-3-oxo-5β-cholestan-(25R)26-oic acid
7α,12α,25-Trihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030105 aka 7α,12α,25-Trihydroxycholest-4-en-3-one
7α,25-Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030107 aka 7α,25-Dihydroxycholest-4-en-3-one, 7a,25-diHCO.
7α,25-Dihydroxy-3-oxocholest-4-en-26-oic acid Metabolite lipidmaps:LMST04030263 aka 7a,25-Dihydroxy-3-oxocholest-4-en-26-oic acid; 7alpha,25-diH,3O-CA
Found in human plasma and cerebrospinal fluid (CSF) [PMID:29960034]; reduced levels found in Alzheimers disease.
7α,12α-Dihydroxy-3-oxochol-4-en-24-oic Metabolite lipidmaps:LMST04010241 aka 7a,12a-Dihydroxy-3-oxochol-4-en-24-oic acid
7α,12α,25-Trihydroxycholest-4-en-3,24-dione Metabolite lipidmaps:LMST04030249 aka 7α,12α,25-Trihydroxycholest-4-en-3,24-dione
Cholic acid Metabolite lipidmaps:LMST04010001
7α,12α,24,25-Tetrahydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030248 aka 7α,12α,24,25-Tetrahydroxycholest-4-en-3-one
7α,24S-Dihydroxycholest-4-en-3-one Metabolite lipidmaps:LMST04030216 aka 7α,24S-Dihydroxycholest-4-en-3-one
7α,24S-Dihydroxy-3-oxocholest-4-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030247 aka 7α,24S-Dihydroxy-3-oxocholest-4-en-26-oic acid
Identified in human plasma [PMID:29960034] and CSF [PMID:30578919,29960034]
7α,24S-Dihydroxycholesterol, Metabolite lipidmaps:LMST04030168 aka 7α,24S-Dihydroxycholesterol,
Found in human plasma [PMID:31009661]
24S-Hydroxycholesterol Metabolite lipidmaps:LMST01010019 AKA (24S)-hydroxycholesterol
Can corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719]
Chenodeoxycholic acid Metabolite lipidmaps:LMST04010032
3β,7β-Dihydroxycholest-5-en(25R)26-oic acid Metabolite lipidmaps:LMST04030235
3β,7β-Dihydroxychol-5-en-24-oic acid Metabolite lipidmaps:LMST04010218
7-Dehydrocholesterol Metabolite lipidmaps:LMST01010069
7-Oxocholesterol Metabolite lipidmaps:LMST01010049
26-Hydroxy-7-oxocholesterol Metabolite lipidmaps:LMST04030180
3β-Hydroxy-7-oxocholest-5-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030239
3β-Hydroxy-7-oxochol-5-en-24-oic acid Metabolite lipidmaps:LMST04010394
3β,5α-Dihydroxycholestan-6-one Metabolite lipidmaps:LMST01010126
SULT2A1 GeneProduct uniprot:Q06520
UGT3A1 GeneProduct uniprot:Q6NUS8
SULT2B1 GeneProduct uniprot:O00204
AKR1C4 GeneProduct hgnc.symbol:AKR1C4
BACS (SLC27A5) GeneProduct hgnc.symbol:SLC27A5 Bile Acid CoA ligase (or synthetase)
microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]
CYP3A4 GeneProduct hgnc.symbol:CYP3A4 CYP3A11 in mouse is responsible for this conversion! [pmid:31698146;11454857]
AKR1D1 GeneProduct hgnc.symbol:AKR1D1 Reduction and oxidation (presumably by AKR1D1 and AKR1C4) may precede before or after 24-hydroxylation.
CYP27A1 GeneProduct hgnc.symbol:CYP27A1
HSD3B7 GeneProduct hgnc.symbol:HSD3B7
CYP8B1 GeneProduct hgnc.symbol:CYP8B1
DBP GeneProduct hgnc.symbol:DBP D-biofinctional protein; aka MFE2, HSD17B4
ACOX2 GeneProduct hgnc.symbol:ACOX2
BAAT GeneProduct hgnc.symbol:BAAT amino acid N-acyl transferase
AMACR GeneProduct hgnc.symbol:AMACR alpha-methylacyl-CoA racemase
broadly expressed [PMID:24309898, 25409824(mouse)]
SCPx (SCP2) GeneProduct hgnc.symbol:SCP2
CYP3A4 GeneProduct hgnc.symbol:CYP3A4 Alternative protein to CH25H for hydroxylation
AKR1D1 GeneProduct hgnc.symbol:AKR1D1
LBP GeneProduct hgnc.symbol:LBP L-bifunctional protein, aka MFP1, enoyl-CoA hydratase and 3-hydroxacyl CoA dehydrogenase EHHADH).
VLCS (SLC27A2) GeneProduct hgnc.symbol:SLC27A2 very-long chain acyl-CoA synthetase
expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]
CYP39A1 GeneProduct hgnc.symbol:CYP39A1 Mostly expressed in liver, also in brain [PMID:24309898,25409824 (mouse)]
AKR1C4 GeneProduct hgnc.symbol:AKR1C4 Reduction and oxidation (presumably by AKR1D1 and AKR1C4) may precede before or after 24-hydroxylation.
INSIG Protein uniprot:O15503
CYP3A4 Protein uniprot:P08684 Reaction also occurs in mouse: CYP3A11
IL-17A Protein uniprot:Q16552 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
CYP7B1 Protein uniprot:O75881
DHCR7 Protein uniprot:Q9UBM7 'ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)'
the 3beta-hydroxysteroid delta7 reductase (DHCR7), which is the regulatory subunit. [https://en.wikipedia.org/wiki/Cholesterol-5,6-oxide_hydrolase]
HSD3B7 Protein uniprot:Q9H2F3
ACOT1 Protein uniprot:Q86TX2
EBI2 Protein uniprot:P32249
LXR-alpha Protein uniprot:P13133
D8D7I Protein uniprot:Q15125 'ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)'
also known as the emopamyl binding protein (EBP), which is the catalytic subunit [https://en.wikipedia.org/wiki/Cholesterol-5,6-oxide_hydrolase]
EBI2 Protein uniprot:P32249 AKA G protein-coupled receptor EBI2 (GPR183)
Estrogen receptor alpha Protein uniprot:P03372 Expressed in vascular cells.
PXR Protein uniprot:O75469
ROR-γt Protein uniprot:F1D8P6 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]
ACOT Protein eccode:3.1.2.2 acyl-CoA thioesterase are a group of enzymes
CYP27A1 Protein uniprot:Q02318
CYP7A1 Protein uniprot:P22680 cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.
'the transcript of which is almost exclusively expressed in liver' [PMID:31698146]
CH25H Protein uniprot:O95992 AKA cholesterol 25-hydroxylase
CYP46A1 Protein uniprot:Q9Y6A2 Responsible for cholesterol homeostasis in brain [PMID:8790411]. Expressed mainly in Brain, however also small quantities in testis and ovary [PMID:24309898,25409824(mouse)].
ChEH Protein uniprot:P34913 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)'
IL-17B Protein uniprot:Q9UHF5 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
IL-17C Protein uniprot:Q9P0M4 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
IL-17D Protein uniprot:Q8TAD2 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
IL-17E Protein uniprot:Q9H293 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
IL-17F Protein uniprot:Q96PD4 'IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases.' [PMID: 25092323]
Estrogen receptor beta Protein uniprot:Q92731 Expressed in vascular cells.
LXR-beta Protein uniprot:P55055
ACOT2 Protein uniprot:P49753 'originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]' [https://www.uniprot.org/uniprot/P49753]
ACOT4 Protein uniprot:Q8N9L9 'Compared to mouse peroxisomal succinyl-coenzyme A thioesterase/ACOT4, the human enzyme has a broad substrate specificity overlapping the activity of three mouse acyl-coenzyme A thioesterases, providing an explanation for the unexpectedly low number of acyl-coenzyme A thioesterase genes in the human genome [PMID:16940157]' [https://www.uniprot.org/uniprot/Q8N9L9]
ACOT6 Protein uniprot:Q3I5F7
ACOT7 Protein uniprot:O00154
ACOT8 Protein uniprot:O14734
ACOT9 Protein uniprot:Q9Y305
ACOT11 Protein uniprot:Q8WXI4
ACOT12 Protein uniprot:Q8WYK0
ACOT13 Protein uniprot:Q9NPJ3
ACOT7L Protein uniprot:Q6ZUV0 'Could be the product of a pseudogene. The peptide used to produce antibodies against ACOT7L matches at 85% with ACOT7 and the antibodies may not be specific to ACOT7L.' [https://www.uniprot.org/uniprot/Q6ZUV0]
ACOT15 Protein uniprot:Q8N1Q8
DHCR7 Protein uniprot:Q9UBM7
HSD11B1 Protein uniprot:P28845
HSD11B2 Protein uniprot:P80365

References

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  23. Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, et al. Am J Hum Genet. 2006 Jun;78(6):1046–52. PubMed Europe PMC Scholia
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