| Summary: | Cerebrotendinous xanthomatosis (CTX) is a rare, recessively inherited lipid storage disease characterized by a markedly reduced production of chenodeoxycholic acid and an increased formation of 25-hydroxylated bile alcohols and cholestanol. Patients with this disease are known to have mutations in the sterol 27-hydroxylase (Cyp27) gene. However, one study showed that mice with a disrupted Cyp27 gene did not have any CTX-related clinical or biochemical abnormalities. To explore the reason, hepatic cholesterol, cholestanol, and 12 intermediates in bile acid biosynthetic pathways were quantified in 10 Cyp27−/− and 7 Cyp27−/− mice, two CTX patients (untreated and treated with chenodeoxycholic acid), and four human control subjects by high resolution gas chromatography-mass spectrometry. Mitochondrial 27-hydroxycholesterol and 5β-cholestane-3α,7α,12α,27-tetrol were virtually absent in both Cyp27−/− mice and CTX patients. In Cyp27−/− mice, microsomal concentrations of intermediates in the early bile acid biosynthetic pathway (7α-hydroxycholesterol, 7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one, and 5β-cholestane-3α,7α,12α-triol), 25-hydroxylated bile alcohols (5β-cholestane-3α,7α,12α,25-tetrol, 5β-cholestane-3α,7α,12α,23R,25-pentol, and 5β-cholestane-3α,7α12α,24R, 25-pentol), and cholestanol were all significantly elevated compared with those in Cyp27−/− mice, although the levels were lower than those in untreated CTX patients. The intermediate levels in early bile acid biosynthesis were more elevated in male (16–86% of CTX) than in female Cyp27−/− mice (7–30% of CTX). In contrast, 25-hydroxylated bile alcohol 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 1) in Cyp27−/− mice, especially in females, classic bile acid biosynthesis via 7α-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. —Honda, A., G. Salen, Y. Matsuzaki, A. K. Batta, G. Xu, E. Leitersdorf, G. S. Tint, S. K. Erickson, N. Tanaka, and S. Shefer. Differences in hepatic levels of intermediates in bile acid biosynthesis between Cyp27−/− mice and CTX.
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