Journal of Lipid Research (May 2003)

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

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

Journal volume & issue
Vol. 44, no. 5
pp. 1001 – 1009

Abstract

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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.

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