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

Journal of Lipid Research

Sandrine Dubrac¹  Ephraim Sehayek¹  Sandra L. Huling²  Meena Ananthanarayanan²  Jaya S. Bollineni³  Fredrick J. Suchy³  Natarajan Balasubramaniyan⁴  Lien Nguyen⁴  Sean Deane⁵  Benjamin Shneider⁵  Ashok K. Batta⁶  Sarah Shefer⁶  David E. Cohen⁷  Steven R. Lear⁷  Gerald Salen⁸  Sandra K. Erickson⁸  Hideyuki Hyogo⁸ 

[1] 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 Medicine, Rockefeller University, New York, NY 10021;Department of Pediatrics, Mount Sinai Medical Center, New York, NY 10029;Department of Veterans Affairs, San Francisco, CA 94121;GI Research Laboratory, Veterans Affairs Medical Center, East Orange, NJ 07018;Liver Center, University of California, San Francisco, CA 94143;Department of Medicine, University of California, San Francisco, CA 94143;

关键词: liver;    intestine;    lipid synthesis;    low density lipoprotein receptors;    sterol 27-hydroxylase;    bile acid transporters;   

DOI  :  

来源: DOAJ

【 摘 要 】

Cholesterol 7α-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.

【 授权许可】

Unknown