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). b35 f5f d0d d0d Reaction also occurs in mouse: CYP3A11 "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] Bile Acid CoA ligase (or synthetase) microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)] d46 aka 7alpha-hydroxycholest-4-en-3-one CYP3A11 in mouse is responsible for this conversion! [pmid:31698146;11454857] Reduction and oxidation (presumably by AKR1D1 and AKR1C4) may precede before or after 24-hydroxylation. AKA 7β,26-dihydroxycholesterol (7β,26-diHC). "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] afa aka 7α,(25S)26-dihydroxycholesterol f5f D-biofinctional protein; aka MFE2, HSD17B4 AKA (25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid "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] afa AKA Dendrogenin A ae1 amino acid N-acyl transferase AKA G protein-coupled receptor EBI2 (GPR183) alpha-methylacyl-CoA racemase broadly expressed [PMID:24309898, 25409824(mouse)] d46 aka (25R)-5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol aka 7α,25-dihydroxycholest-4-en-3-one Alternative protein to CH25H for hydroxylation f5f a9c Expressed in vascular cells. aka 7α-Hydroxy-3-oxocholest-4-en-(25S)26-oyl-CoA AKA 24S-hydroxycholesterol Can corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719] aka 7α-Hydroxy-3-oxocholest-4-en-(25R)26-oyl-CoA aka 7α,12α,(25R)26-TriHydroxy-5β-cholestan-3-one L-bifunctional protein, aka MFP1, enoyl-CoA hydratase and 3-hydroxacyl CoA dehydrogenase EHHADH). Aka 3β,7α-dihydroxycholest-5-en-(25R)26-oic acid f5f aka 7α,25-dihydroxycholesterol "the most potent EBI2 agonist 7α,25-dihydroxycholesterol (7α,25-diHC))" [PMID:31698146] b97 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] dc7 aka 7α-hydroxycholest-4-en-3-one f5f acyl-CoA thioesterase are a group of enzymes very-long chain acyl-CoA synthetase expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)] d46 AKA 5,6α-epoxycholesterol AKA cholestane-3β,5α,6β-triol "Biomarker for NPC1; elevated levels of cholestane-3β,5α,6β-triol in plasma from NPC1 patients." [PMID: 21048217]. AKA 7β-hydroxycholesterol (7β-HC) AKA 7α-hydroxycholesterol (7α-HC) AKA 25-Hydroxycholesterol Produced by macrophages [PMID: 19805370, 19502589, 23273843], in vivo [PMID: 25104388]. ad6 c09 a56 b7e AKA 7α,25-Dihydroxycholesterol Involved in immune response (agonist of G-protein-coupled receptor EBI2 (AKA GPR183)) [PMID: 21796212, 21796211]. b56 e9d "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] f5f c13 AKA 7α,26-dihydroxycholesterol; 7-alpha, (25R)26-diHC ebf c8b f5f ebf c8b cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. "the transcript of which is almost exclusively expressed in liver" [PMID:31698146] f5f ebf c8b f5f f5f AKA cholesterol 25-hydroxylase f5f Responsible for cholesterol homeostasis in brain [PMID:8790411]. Expressed mainly in Brain, however also small quantities in testis and ovary [PMID:24309898,25409824(mouse)]. d46 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)" ae1 "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] "IL-17 familiy is essential in host defense and may play key pathogenic roles in autoimmune diseases." [PMID: 25092323] Expressed in vascular cells. 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] f5f AKA 7α-hydroxycholesterol (7α-HC) aka 7α,(25S)26-dihydroxycholest-4-en-3-one aka 7alpha,12alpha-dihydroxy-5beta-cholestan-3-one aka 5beta-cholestane-3alpha,7alpha,12alpha-triol ; trihydroxycoprostane ebf c8b f5f "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] f5f eae ebf c8b f5f aka (25R)-7alpha,26-dihydroxycholest-4-en-3-one f5f aka 7-Hydroxy-3-oxocholest-4-en-(25R)26-oic acid f5f aka 7alpha,12alpha,(25R)26-trihydroxycholest-4-en-3-one f5f aka 7-alpha,12-alpha-diHydroxy-3-oxocholest-4-en-(25R)26-oic acid (not available in Wikidata) f5f aka 7α,12α-diHydroxy-3-oxo-5β-cholestan-(25R)26-oic acid aka 7α,12α,25-Trihydroxycholest-4-en-3-one aka 7α,25-Dihydroxycholest-4-en-3-one, 7a,25-diHCO. 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. e17 aka 7a,12a-Dihydroxy-3-oxochol-4-en-24-oic acid aka 7α,12α,25-Trihydroxycholest-4-en-3,24-dione aka 7α,12α,24,25-Tetrahydroxycholest-4-en-3-one aka 7α,24S-Dihydroxycholest-4-en-3-one Mostly expressed in liver, also in brain [PMID:24309898,25409824 (mouse)] d46 aka 7α,24S-Dihydroxy-3-oxocholest-4-en-26-oic acid Identified in human plasma [PMID:29960034] and CSF [PMID:30578919,29960034] e51 e17 aka 7α,24S-Dihydroxycholesterol, Found in human plasma [PMID:31009661] f84 Reduction and oxidation (presumably by AKR1D1 and AKR1C4) may precede before or after 24-hydroxylation. AKA (24S)-hydroxycholesterol Can corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719] aka 7-Hydroxy-3-oxocholest-4-en-(25R)26-oic acid f5f "originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]" [https://www.uniprot.org/uniprot/P49753] f07 a7b "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] a7b "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] Bile Acid CoA ligase (or synthetase) microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)] d46 very-long chain acyl-CoA synthetase expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)] d46 Bile Acid CoA ligase (or synthetase) microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)] d46 alpha-methylacyl-CoA racemase broadly expressed [PMID:24309898, 25409824(mouse)] d46 D-biofinctional protein; aka MFE2, HSD17B4 acyl-CoA thioesterase are a group of enzymes ebf c8b ebf c8b d0d EC:2.8.2.2 b73 d0d EC:2.8.2.2 d0d d0d c87 ae2 Dimer formation Research findings in Mouse (Mus musculus. b3c "ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)" "(25R)26-HC is a selective estrogen receptor (ER) modulator, expressed in vascular cells." [PMID: 17873880] da0 f43 e2d f4d f43 bec dbb ae6 c87 f5f c6d ae1 Research findings in Mouse (Mus musculus). b3c reduction reaction f5f Reaction also occurs in mouse: CYP3A11 f5f f5f ae1 f5f oxidation f5f f5f ae1 f5f "7α,25-diHC is a potent agonist of the G protein-coupled receptor EBI2 (GPR183). 7α,25-diHC acts as a chemoattractant for immune cells expressing EBI2 by directing cell migration." Research findings in Mouse (Mus musculus) . [PMID: PubMed 21796212., 21796211]. b56 e9d "7β,26-dihydroxycholesterol (7β,26-diHC), presumably the 25R-epimer, as a potent agonist for RORγt" Research findings in Mouse (Mus musculus) . b3c f5f f5f b97 aminolysis reaction ae1 ae1 eae d21 d74 da7 f5f eae b5f f5f cf0 eae d70 a51 c74 f5f f5f (25R)26-hydroxylated 7α-hydroxylation d33 ab4 d68 f5f d46 "7β,26-dihydroxycholesterol (7β,26-diHC), presumably the 25R-epimer, as a potent agonist for RORγt" Research findings in Mouse (Mus musculus) . b3c Research findings in Mouse (Mus musculus. b3c (25R)26-carboxylated f5f f5f f5f b97 f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f f5f d46 f5f d70 f5f f5f f5f a9c Exact route for metabolism of 7alpha,25-diHCO are still to be fully established [PMID:31698146] f5f f5f f5f e2c f5f f5f e2c f5f e51 f5f e51 e51 bec dbb ae6 bec dbb ae6 c6d f5f f5f double bond with E stereochemistry between C-24 and C-25 f5f hydrolysis f5f oxidised by HSD activity of DBP f5f f5f f5f af3 fd2 f5f f5f f5f f5f f5f f5f af3 fd2 ae1 "7α,25-diHC is a potent agonist of the G protein-coupled receptor EBI2 (GPR183). 7α,25-diHC acts as a chemoattractant for immune cells expressing EBI2 by directing cell migration." 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