Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice.
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.
Erickson
Sandra K
SK
Department of Medicine, University of California, San Francisco, CA 94143, USA. skerick@itsa.ucsf.edu
Lear
Steven R
SR
Deane
Sean
S
Dubrac
Sandrine
S
Huling
Sandra L
SL
Nguyen
Lien
L
Bollineni
Jaya S
JS
Shefer
Sarah
S
Hyogo
Hideyuki
H
Cohen
David E
DE
Shneider
Benjamin
B
Sehayek
Ephraim
E
Ananthanarayanan
Meena
M
Balasubramaniyan
Natarajan
N
Suchy
Fredrick J
FJ
Batta
Ashok K
AK
Salen
Gerald
G
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
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