Differences in hepatic levels of intermediates in bile acid biosynthesis between Cyp27(-/-) mice and CTX

Cerebrotendinous xanthomatosis (CTX) is a rare, recessively inherited lipid storage disease characterized by a markedly reduced production of chenodeo xycholic acid and an increased formation of 25-hydroxylated bile alcohols a nd cholestanol, Patients with this disease are known to have mutations in t he sterol 27-hydroxylase (Cyp27) gene, However, one study showed that mice with a disrupted Cyp27 gene did not have any CTX-related clinical or bioche mical abnormalities, To explore the reason, hepatic cholesterol, cholestano l, and 12 intermediates in bile acid biosynthetic pathways were quantified in 10 Cyp27(-/-) and 7 Cyp27(+/+) mice, two CTX patients (untreated and tre ated with chenodeoxycholic acid), and four human control subjects by high r esolution gas chromatography-mass spectrometry. Mitochondrial 27-hydroxycho lesterol and 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha ,27-tetrol were virtually absent in both Cyp27(-/-) mice and CTX patients, In Cyp27(-/-) mi ce, microsomal concentrations of intermediates in the early bile acid biosy nthetic pathway (7 alpha -hydroxycholesterol, 7 alpha -hydroxy-4-cholesten- 3-one, 7 alpha, 12 alpha -dihydroxy-4-chtolesten-3-one, and 5 beta -cholest ane-3 alpha ,7 alpha, 12 alpha -triol), 25-hydroxylated bile alcohols (5 be ta -cholestane-3 alpha ,7 alpha ,12 alpha ,25-tetrol, 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha ,23R,25-pentol, and 5 beta -cholestane-3 alpha ,7 alpha ,12 alpha ,24R, 25-pentol), and cholestanol were all significantly el evated compared with those in Cyp27(+/+) mice, although the levels were low er than those in untreated CTX patients, The intermediate levels in early b ile acid biosynthesis were more elevated in male (16-86% of CTX) than in fe male Cyp27(-/-) mice (7-30% of CTX), In contrast, 25-hydroxylated bile alco hol concentrations were not significantly different between male and female Cyp27(-/-) mice and were considerably lower (less than 14%) than those in CTX patients. These results suggest that I) in Cyp27(-/-) mice, especially in females, classic bile acid biosynthesis via 7 alpha -hydroxycholesterol is not stimulated as much as in CTX patients; and 2) formed 25-hydroxylated bile alcohols are more efficiently metabolized in Cyp27(-/-) mice than in CTX patients.