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Journal of Lipid Research, Vol. 44, 1001-1009, May 2003
Copyright © 2003 by Lipid Research, Inc.

Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice

Sandra K. Erickson^1,*,,, Steven R. Lear^*, Sean Deane^2,*, Sandrine Dubrac^*, Sandra L. Huling, Lien Nguyen^**, Jaya S. Bollineni^**, Sarah Shefer^**, Hideyuki Hyogo^3,, David E. Cohen, Benjamin Shneider, Ephraim Sehayek^***, Meena Ananthanarayanan, Natarajan Balasubramaniyan, Fredrick J. Suchy, Ashok K. Batta and Gerald Salen^**,

^* Department of Medicine, University of California, San Francisco, CA 94143
Liver Center, University of California, San Francisco, CA 94143
Department of Veterans Affairs, San Francisco, CA 94121
^** Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461
Department of Pediatrics, Mount Sinai Medical Center, New York, NY 10029
^*** Department of Medicine, Rockefeller University, New York, NY 10021
GI Research Laboratory, Veterans Affairs Medical Center, East Orange, NJ 07018

¹ To whom correspondence should be addressed. e-mail: skerick{at}itsa.ucsf.edu

Cholesterol 7-hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1, encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile.

Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.

Supplementary key words liver • intestine • lipid synthesis • low density lipoprotein receptors • sterol 27-hydroxylase • bile acid transporters • fatty acids

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