Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders

Abstract Cholestane-3β,5α,6β- triol(3β,5α,6β- triol) is formed from cholestan-5,6-epoxide (5,6-EC) in a reaction catalysed by cholesterol epoxidehydrolase, following formation of 5,6-EC through free radical oxidation of cholesterol. 7-Oxocholesterol (7-OC) and 7β-hydroxycholesterol (7β-HC) can also be formed by free radical oxidation of cholesterol. Here we investigate how 3β,5α,6β- triol, 7-OC and 7β-HC are metabolised to bile acids. We show, by monitoring oxysterolmetabolites in plasma samples rich in 3β,5α,6β- triol, 7-OC and 7β-HC, that these three oxysterolsfall into novel branches of the acidic pathway of bile acid biosynthesisbecoming (25R)26-hydroxylated then carboxylated, 24-hydroxylated and side-chain shortened to give the final products 3β,5α,6β-trihydroxycholanoic, 3β-hydroxy-7-oxochol-5-enoic and 3β,7β-dihydroxychol-5-enoic acids, respectively. The intermediates in these pathways may be causative of some phenotypical features of, and/or have diagnostic value for, the lysosomal storage diseases, Niemann Pick types C and B and lysosomal acid lipase deficiency. Free radical derived oxysterolsare metabolised in human to unusual bile acidsvia novel branches of the acidic pathway, intermediates in these pathways are observed in plasma.