J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400219-JLR200 on November 1, 2004

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Journal of Lipid Research, Vol. 46, 76-85, January 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Role of CYP27A in cholesterol and bile acid metabolism

Sandrine Dubrac*, Steven R. Lear*,{dagger}, Meena Ananthanarayanan§, Natarajan Balasubramaniyan§, Jaya Bollineni**, Sarah Shefer**, Hideyuki Hyogo{dagger}{dagger}, David E. Cohen§§, Patricia J. Blanche***, Ronald M. Krauss***, Ashok K. Batta{dagger}{dagger}{dagger}, Gerald Salen**, Frederick J. Suchy§, Nobuyo Maeda§§§ and Sandra K. Erickson1,*,{dagger},****

* Department of Medicine, University of California, San Francisco, CA 94143
**** Liver Center, University of California, San Francisco, CA 94143
{dagger} Department of Veterans Affairs, San Francisco, CA, 94121
§ Department of Pediatrics, Mount Sinai Medical Center, New York, NY 10029
** Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
{dagger}{dagger} Department of General Medicine, Hiroshima University Hospital, Hiroshima, Japan
§§ Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461
*** Donner Laboratory, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
{dagger}{dagger}{dagger} GI Research Laboratory, Veterans Affairs Medical Center, East Orange, NJ 07018
§§§ Department of Pathology, University of North Carolina, Chapel Hill, NC 27599

1 To whom correspondence should be addressed. e-mail: 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 the roles of CYP27A in the 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 weight 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 was in homozygotes, suggesting that 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 increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected.

Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.

Supplementary key words liver • lipoproteins • lipid synthesis • fatty acids • bile alcohols • cyp7A • transporters • receptors • gender


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