title: Role of CYP27A in cholesterol and bile acid metabolism.
abstract: 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.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dubrac
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lear
authors.forename: Meena
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: Natarajan
authors.initials: N
authors.lastname: Balasubramaniyan
authors.forename: Jaya
authors.initials: J
authors.lastname: Bollineni
authors.forename: Sarah
authors.initials: S
authors.lastname: Shefer
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hyogo
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Blanche
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Batta
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Suchy
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Erickson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D002784:Cholesterol; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse