Role of CYP27A in cholesterol and bile acid metabolism.
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.
Dubrac
Sandrine
S
Department of Medicine, University of California, San Francisco, CA 94143, USA.
Lear
Steven R
SR
Ananthanarayanan
Meena
M
Balasubramaniyan
Natarajan
N
Bollineni
Jaya
J
Shefer
Sarah
S
Hyogo
Hideyuki
H
Cohen
David E
DE
Blanche
Patricia J
PJ
Krauss
Ronald M
RM
Batta
Ashok K
AK
Salen
Gerald
G
Suchy
Frederick J
FJ
Maeda
Nobuyo
N
Erickson
Sandra K
SK
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*
D001647:Bile Acids and Salts; D005227:Fatty Acids; D002784:Cholesterol; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse