title: Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice.
abstract: Cholesterol 7alpha-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.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA. skerick@itsa.ucsf.edu
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Erickson
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lear
authors.forename: Sean
authors.initials: S
authors.lastname: Deane
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dubrac
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Huling
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.forename: Jaya S
authors.initials: JS
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: Benjamin
authors.initials: B
authors.lastname: Shneider
authors.forename: Ephraim
authors.initials: E
authors.lastname: Sehayek
authors.forename: Meena
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: Natarajan
authors.initials: N
authors.lastname: Balasubramaniyan
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Suchy
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Batta
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D008055:Lipids; D012333:RNA, Messenger; D011973:Receptors, LDL; D013261:Sterols; D002784:Cholesterol; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse