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Journal of Lipid Research, Vol. 44, 1956-1962, October 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

FXR-mediated down-regulation of CYP7A1 dominates LXR in long-term cholesterol-fed NZW rabbits

Guorong Xu^1,*,, Hai Li, Lu-xing Pan, Quan Shang, Akira Honda, M. Ananthanarayanan^**, Sandra K. Erickson, Benjamin L. Shneider^**, Sarah Shefer, Jaya Bollineni, Barry M. Forman, Yasushi Matsuzaki, Frederick J. Suchy^**, G. Stephen Tint^*, and Gerald Salen^*,

^* Medical Service, Veteran's Administration Medical Center, East Orange, NJ 07018
Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
GI Division, University of Tsukuba, School of Medicine, Tsukuba City 305-8575, Japan
^** Department of Pediatrics, Mt. Sinai School of Medicine, New York, NY 10029
Department of Medicine, University of California, San Francisco and Veteran's Administration Medical Center, San Francisco, CA 94121
Department of Molecular Medicine, The City of Hope National Medical Center, Duarte, CA 91010

¹ To whom correspondence should be addressed. e-mail: xugu{at}umdnj.edu

We investigated how cholesterol feeding regulates cholesterol 7-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor (LXR) in New Zealand white rabbits. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, mRNA levels of the FXR target genes short-heterodimer partner (SHP) and sterol 12-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. In contrast, the mRNA levels of the LXR target genes ATP binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) increased 5-fold and 2.3-fold, respectively, associated with significant increases in hepatic concentrations of oxysterols. Activity and mRNA levels of CYP7A1 increased 2.4 times and 2.2 times, respectively. After 10 days of cholesterol feeding, the bile acid pool size increased nearly 2-fold. SHP mRNA levels increased 4.1-fold while CYP8B declined 64%. ABCA1 mRNA rose 8-fold and CETP mRNA remained elevated. Activity and mRNA of CYP7A1 decreased 60% and 90%, respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size or change FXR activation, while LXR was activated highly secondary to increased hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXR.

Thus, in rabbits, when FXR and LXR are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXR to suppress CYP7A1 mRNA expression.

Supplementary key words dietary cholesterol • oxysterol • short-heterodimer partner • ATP binding cassette transporter A1

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