SCHEME 4.

Suggested pathways for biosynthesis of bile acids found in CSF. The acidic pathway starts with 26-hydroxylation of cholesterol by CYP27A1, and the 24(S)-hydroxycholesterol pathway by 24(S)-hydroxylation of cholesterol by CYP46A1. Compounds drawn in black are identified in CSF, those in blue are presumptively identified, and those in red were not detected or were present in trace quantities only. With the exception of α-methylacyl-CoA racemase (necessary for the acidic pathway), all of the enzymes (or mRNA transcripts) required for the formation of 7α-hydroxy-3-oxochol-4-en-24-oic acid are present in brain. Abbreviations, Swiss-Prot accession number, and reference to the enzyme, where applicable (or mRNA transcript), in brain are as follows: CYP27A1, cytochrome P450 27A1, Q02318 (54); CYP46A1, cytochrome P450 46A1, Q9Y6A2 (48); CYP7B1, cytochrome P450 7B1, O75881 (75); CYP39A1, cytochrome P450 39A1, Q9NYL5 (53); HSD3B7, 3β-hydroxysteroid dehydrogenase type 7, Q9H2F3 (24); VLCS, very long chain acyl-CoA synthetase, O35488 (56); AMACR, α-methylacyl-CoA racemase, Q9UHK6; BCOX, branched chain acyl-CoA oxidase, Q99424 (76); DBP, d-bifunctional protein, P51659 (57); LBP, l-bifunctional protein, Q08426 (57); SCPx, sterol carrier protein x, P22307 (77). Metabolites identified as LXRα ligands in SN4741 cells are indicated by LXR+.