J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M600120-JLR200 on April 11, 2006

Papers In Press, published online ahead of print July 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600120-JLR200
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Journal of Lipid Research, Vol. 47, 1513-1520, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Transgenic expression of CYP7A1 in LDL receptor-deficient mice blocks diet-induced hypercholesterolemiaboxs

Eric P. Ratliff, Alejandra Gutierrez and Roger A. Davis1

Heart Institute, BioScience Center, San Diego State University, San Diego, CA 92182

boxs The online version of this article (available at http://www.jlr.org) contains an additional figure.

Published, JLR Papers in Press, April 11, 2006.

1 To whom correspondence should be addressed. e-mail: rdavis{at}sunstroke.sdsu.edu

Constitutive expression of a cholesterol-7{alpha}-hydroxylase (CYP7A1) transgene in LDL receptor-deficient mice blocked the ability of a cholesterol-enriched diet to increase plasma levels of apolipoprotein B-containing lipoproteins. LDL receptor-deficient mice expressing the CYP7A1 transgene exhibited complete resistance to diet-induced hypercholesterolemia and to the accumulation of cholesterol in the liver. Hepatic mRNA expression of liver X receptor-inducible ABCG5 and ABCG8 was decreased in CYP7A1 transgenic, LDL receptor-deficient mice fed a cholesterol-enriched diet. Thus, increased biliary cholesterol excretion could not account for the maintenance of cholesterol homeostasis. CYP7A1 transgenic, LDL receptor-deficient mice fed the cholesterol-enriched diet exhibited decreased jejunal Niemann-Pick C1-Like 1 protein (NPC1L1) mRNA expression, an important mediator of intestinal cholesterol absorption. A taurocholate-enriched diet also decreased NPC1L1 mRNA expression in a farnesoid X receptor-independent manner. Reduced expression of NPC1L1 mRNA was associated with decreased cholesterol absorption (~20%; P < 0.05) exhibited by CYP7A1 transgenic LDL receptor-deficient mice fed the cholesterol-enriched diet. The combined data show that enhanced expression of CYP7A1 is an effective means to prevent the accumulation of cholesterol in the liver and of atherogenic apolipoprotein B-containing lipoproteins in plasma.

Supplementary key words cholesterol-7{alpha}-hydroxylase • bile acids • cholesterol • low density lipoprotein receptors • proprotein convertase subtilisin/kexin type 9 • Niemann-Pick C1-Like 1 protein

Abbreviations: CYP7A1, cholesterol-7{alpha}-hydroxylase; FXR, farnesoid X receptor; LXR, liver X receptor; NPC1L1, Niemann-Pick C1-Like 1 protein; SREBP, sterol-regulatory element binding protein


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Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.