Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27- hydroxylase gene

Haim Rosen, Ayeleth Reshef, Nobuyo Maeda, Andrea Lippoldt, Shoshi Shpizen, Liat Triger, Gösta Eggertsen, Ingemar Björkhem, Eran Leitersdorf*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

223 Scopus citations

Abstract

Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7α-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7α-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.

Original languageAmerican English
Pages (from-to)14805-14812
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number24
DOIs
StatePublished - 12 Jun 1998

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