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Journal of Lipid Research, Vol. 42, 291-300, February 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

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

Correspondence to: Gerald Salen, at the GI Laboratory (15A), VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095., Salenge{at}UMDNJ.edu (E-mail)

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 5ß-cholestane-3,7,12,27-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 (7-hydroxycholesterol, 7-hydroxy-4-cholesten-3-one, 7,12-dihydroxy-4-cholesten-3-one, and 5ß-cholestane-3,7,12-triol), 25-hydroxylated bile alcohols (5ß-cholestane-3,7,12,25-tetrol, 5ß-cholestane-3,7,12,23R,25-pentol, and 5ß-cholestane-3,7,12,24R, 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 7-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. J. Lipid Res. 2001. 42: 291;–300.

Supplementary key words: cholesterol, cholestanol, bile alcohols

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