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A more recent version of this article appeared on January 1, 2005

Papers In Press, published online ahead of print November 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400219-JLR200
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Submitted on June 14, 2004
Revised on October 18, 2004
Accepted on October 18, 2004

Role of CYP27A in cholesterol and bile acid metabolism

Sandrine Dubrac, Steven R. Lear, Meena Ananthanarayanan, Natarajan Balasubramaniyan, Jaya Bollineni, Sarah Shefer, Hideyuki Hyogo, David E. Cohen, Patricia J. Blanche, Ronald M. Krauss, Ashok K. Batta, Gerald Salen, Frederick J. Suchy, Nobuyo Maeda, and Sandra K. Erickson

VAMC-111F, San Francisco, CA 94121

Corresponding Author: skerick{at}itsa.ucsf.edu

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into roles of CYP27A in regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous and wild type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weights and were mildly hypercholesterolemic with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes, but it was in homozygotes suggesting parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were elevated; however, side chain cleavage was impaired leading to decreased bile salt concentrations in gallbladder bile. Expression of Ntcp, the major sinusoidal bile salt transporter was increased and that of Bsep, the major canalicular bile salt transporter, decreased. Gender played a modifying role in homozygous response to cyp27A deficiency, with females being generally more severely impacted. Thus, both cyp27A genotype and gender impacted regulation of hepatic bile acid, cholesterol and fatty acid metabolism.


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