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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 hypercholesterolemia

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

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

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-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-hydroxylase • bile acids • cholesterol • low density lipoprotein receptors • proprotein convertase subtilisin/kexin type 9 • Niemann-Pick C1-Like 1 protein

Abbreviations: CYP7A1, cholesterol-7-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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