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).b35f5fd0dd0dReaction 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)]d46aka 7alpha-hydroxycholest-4-en-3-oneCYP3A11 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]afaaka 7α,(25S)26-dihydroxycholesterolf5fD-biofinctional protein; aka MFE2, HSD17B4AKA (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]afaAKA Dendrogenin Aae1amino acid N-acyl transferaseAKA G protein-coupled receptor EBI2 (GPR183)alpha-methylacyl-CoA racemasebroadly expressed [PMID:24309898, 25409824(mouse)]d46aka (25R)-5beta-cholestane-3alpha,7alpha,12alpha,26-tetrolaka 7α,25-dihydroxycholest-4-en-3-oneAlternative protein to CH25H for hydroxylationf5fa9cExpressed in vascular cells.aka 7α-Hydroxy-3-oxocholest-4-en-(25S)26-oyl-CoAAKA 24S-hydroxycholesterolCan corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719]aka 7α-Hydroxy-3-oxocholest-4-en-(25R)26-oyl-CoAaka 7α,12α,(25R)26-TriHydroxy-5β-cholestan-3-oneL-bifunctional protein, aka MFP1, enoyl-CoA hydratase and 3-hydroxacyl CoA dehydrogenase EHHADH).Aka 3β,7α-dihydroxycholest-5-en-(25R)26-oic acidf5faka 7α,25-dihydroxycholesterol"the most potent EBI2 agonist 7α,25-dihydroxycholesterol (7α,25-diHC))" [PMID:31698146]b97AKA 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]dc7aka 7α-hydroxycholest-4-en-3-onef5facyl-CoA thioesterase are a group of enzymesvery-long chain acyl-CoA synthetaseexpressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]d46AKA 5,6α-epoxycholesterolAKA 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-HydroxycholesterolProduced by macrophages [PMID: 19805370, 19502589, 23273843], in vivo [PMID: 25104388].ad6c09a56b7eAKA 7α,25-DihydroxycholesterolInvolved in immune response (agonist of G-protein-coupled receptor EBI2 (AKA GPR183)) [PMID: 21796212, 21796211].b56e9d"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]f5fc13AKA 7α,26-dihydroxycholesterol; 7-alpha, (25R)26-diHCebfc8bf5febfc8bcholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis."the transcript of which is almost exclusively expressed in liver" [PMID:31698146]f5febfc8bf5ff5fAKA cholesterol 25-hydroxylasef5fResponsible for cholesterol homeostasis in brain [PMID:8790411]. Expressed mainly in Brain, however also small quantities in testis and ovary [PMID:24309898,25409824(mouse)].d46AKA 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]f5fAKA 7α-hydroxycholesterol (7α-HC)aka 7α,(25S)26-dihydroxycholest-4-en-3-oneaka 7alpha,12alpha-dihydroxy-5beta-cholestan-3-oneaka 5beta-cholestane-3alpha,7alpha,12alpha-triol ; trihydroxycoprostaneebfc8bf5f"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]f5feaeebfc8bf5faka (25R)-7alpha,26-dihydroxycholest-4-en-3-onef5faka 7-Hydroxy-3-oxocholest-4-en-(25R)26-oic acidf5faka 7alpha,12alpha,(25R)26-trihydroxycholest-4-en-3-onef5faka 7-alpha,12-alpha-diHydroxy-3-oxocholest-4-en-(25R)26-oic acid (not available in Wikidata)f5faka 7α,12α-diHydroxy-3-oxo-5β-cholestan-(25R)26-oic acidaka 7α,12α,25-Trihydroxycholest-4-en-3-oneaka 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-CAFound in human plasma and cerebrospinal fluid (CSF) [PMID:29960034]; reduced levels found in Alzheimers disease.e17aka 7a,12a-Dihydroxy-3-oxochol-4-en-24-oic acidaka 7α,12α,25-Trihydroxycholest-4-en-3,24-dioneaka 7α,12α,24,25-Tetrahydroxycholest-4-en-3-oneaka 7α,24S-Dihydroxycholest-4-en-3-oneMostly expressed in liver, also in brain [PMID:24309898,25409824 (mouse)]d46aka 7α,24S-Dihydroxy-3-oxocholest-4-en-26-oic acidIdentified in human plasma [PMID:29960034] and CSF [PMID:30578919,29960034]e51e17aka 7α,24S-Dihydroxycholesterol,Found in human plasma [PMID:31009661]f84Reduction and oxidation
(presumably by AKR1D1 and AKR1C4)
may precede before or after 24-hydroxylation.AKA (24S)-hydroxycholesterolCan corss the Blood-Brain-Barrier (to remove cholesterol from brain tissue) [PMID:8790411; 9717719]aka 7-Hydroxy-3-oxocholest-4-en-(25R)26-oic acidf5f"originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]" [https://www.uniprot.org/uniprot/P49753]f07a7b"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)]d46very-long chain acyl-CoA synthetaseexpressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]d46Bile Acid CoA ligase (or synthetase)microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]d46alpha-methylacyl-CoA racemasebroadly expressed [PMID:24309898, 25409824(mouse)]d46D-biofinctional protein; aka MFE2, HSD17B4acyl-CoA thioesterase are a group of enzymesebfc8bebfc8bd0dEC:2.8.2.2b73d0dEC:2.8.2.2d0dd0dc87ae2Dimer formationResearch 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]da0f43e2df4df43becdbbae6c87f5fc6dae1Research findings in Mouse (Mus musculus).b3creduction reactionf5fReaction also occurs in mouse: CYP3A11f5ff5fae1f5foxidationf5ff5fae1f5f"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].b56e9d"7β,26-dihydroxycholesterol (7β,26-diHC), presumably the 25R-epimer, as a potent agonist for RORγt" Research findings in Mouse (Mus musculus) .b3cf5ff5fb97aminolysis reactionae1ae1eaed21d74da7f5feaeb5ff5fcf0eaed70a51c74f5ff5f(25R)26-hydroxylated7α-hydroxylationd33ab4d68f5fd46"7β,26-dihydroxycholesterol (7β,26-diHC), presumably the 25R-epimer, as a potent agonist for RORγt" Research findings in Mouse (Mus musculus) .b3cResearch findings in Mouse (Mus musculus.b3c(25R)26-carboxylatedf5ff5ff5fb97f5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5ff5fd46f5fd70f5ff5ff5fa9cExact route for metabolism of 7alpha,25-diHCO are still to be fully established [PMID:31698146]f5ff5ff5fe2cf5ff5fe2cf5fe51f5fe51e51becdbbae6becdbbae6c6df5ff5fdouble bond with E stereochemistry between C-24 and C-25f5fhydrolysisf5foxidised by HSD activity of DBPf5ff5ff5faf3fd2f5ff5ff5ff5ff5ff5faf3fd2ae1"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) . 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