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Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE‐knockout mice
Author(s) -
Zurkinden Line,
Solca Curzio,
Vögeli Isabelle A.,
Vogt Bruno,
Ackermann Daniel,
Erickson Sandra K.,
Frey Felix J.,
Sviridov Dmitri,
Escher Geneviève
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-233791
Subject(s) - cyp27a1 , apolipoprotein e , endocrinology , medicine , cholesterol , knockout mouse , cerebrotendinous xanthomatosis , apolipoprotein b , very low density lipoprotein , lipoprotein , cholesterol 7 alpha hydroxylase , biology , chemistry , receptor , disease
In humans, sterol 27‐hydroxylase (CYP27A1) deficiency leads to cholesterol deposition in tendons and vasculature. Thus, in addition to its role in bile acid synthesis, where it converts cholesterol to 27‐hydroxycholesterol (27‐OHC), CYP27A1 may also be atheroprotective. Cyp27A1‐deficient ( Cyp27A1 –/– ) mice were crossed with apolipoprotein E (apoE)‐deficient mice. Cyp27A1 +/+ /apoE –/– [ApoE‐knockout (KO)], Cyp27A1 +/– / apoE –/– heterozygous (het), and Cyp27A1 –/– / apoE –/– [double‐knockout (DKO)] mice were challenged with a Western diet (WD) for 3 and 6 mo. ApoE‐KO mice fed a chow diet or a WD were used as the control. The severity of atherosclerosis in DKO mice was reduced 10‐fold. Compared with the control, the DKO mice had no 27‐OHC, total plasma cholesterol and low‐density lipoprotein and very low density lipoprotein (LDL/VLDL) concentrations were reduced 2‐fold, and HDL was elevated 2‐fold. Expression of hepatic CYP7A1, CYP3A, and CYP8B1 were 5‐ to 10‐fold higher. 3‐Hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMGR) activity increased 4‐fold. Fecal cholesterol was increased. In contrast, het mice fed a WD developed accelerated atherosclerosis and severe skin lesions, possibly because of reduced reverse cholesterol transport due to diminished 27‐OHC production. CYP27A1 activity is involved in the control of cholesterol homeostasis and development of atherosclerosis with a distinct gene dose‐dependent effect.—Zurkinden, L., Solcà, C., Vögeli, I. A., Vogt, B., Ackermann, D., Erickson, S. K., Frey, F. J., Sviridov, D., Escher, G. Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE‐knockout mice. FASEB J. 28, 1198–1209 (2014). www.fasebj.org