Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model. Evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis.
CYP27-overexpressed transgenic mice were generated with the use of a human full-length CYP27 coding region cloned into a ubiquitous expression vector. Positive transgenic mice were identified by tail DNA genotyping and high fecal 27-hydroxycholesterol content. The levels of 27-hydroxycholesterol were found to be 3-5 times higher in the circulation and the tissues of the overexpressed mice when compared with littermate controls. There were no gross morphological differences between the overexpressed mice and their controls. Total cholesterol and triglyceride levels were not affected by overexpression of CYP27. Serum lathosterol was also normal, suggesting a normal rate of cholesterol synthesis. Serum levels of 7alpha-hydroxycholesterol were unaffected, suggesting a normal rate of bile acid formation in the pathway involving cholesterol 7alpha-hydroxylase. Biliary bile acid composition was slightly affected by CYP27 overexpression in female but not in male mice. Fecal levels of neutral steroids were slightly but significantly increased in overexpressor female mice but not in male mice. Levels of 24-hydroxycholesterol in the circulation were significantly reduced in the overexpressed mice, probably as a consequence of a recently described catabolic pathway involving CYP27. Combined with the results of our previous work on mice with a disruption of the CYP27 gene, the present results suggest that the levels of 27-hydroxycholesterol are not of critical importance for cholesterol homeostasis in mice.
Department of Pathology, Hadassah University Hospital, 91120 Jerusalem, Israel..
Karen
K
Meir
Daniel
D
Kitsberg
Irit
I
Alkalay
Fanny
F
Szafer
Haim
H
Rosen
Shoshanna
S
Shpitzen
Liat Ben
LB
Avi
Bart
B
Staels
Catherine
C
Fievet
Vardiella
V
Meiner
Ingemar
I
Björkhem
Eran
E
Leitersdorf
D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D005243:Feces / Q000737:chemistry; D005260:Female; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D013250:Steroid Hydroxylases / Q000235:genetics / Q000502:physiology*
D001647:Bile Acids and Salts; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse