Farnesoid X receptor-mediated downregulation of CYP7A1 dominates LXRalpha  in long-term cholesterol-fed NZW rabbits

doi:10.1194/jlr.M300182-JLR200

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Farnesoid X receptor-mediated downregulation of CYP7A1 dominates LXR $alpha$ in long-term cholesterol-fed NZW rabbits

Guorong Xu, Hai Li, Luxing Pan, Quan Shang, Akira Honda, M Ananthanarayanan, Sandra K. Erickson, Benjamin L. Shneider, Sarah Shefer, Jaya Bollineni, Barry M. Forman, Yasushi Matsuzaki, Frederik J. Suchy, G. Stephen Tint, and Gerald Salen

Dept of Medicine, University of Medicine & Dentistry of New Jersey, NJ Medical School, East Orange, NJ 07018-1095

Corresponding Author: xugu{at}umdnj.edu

We investigated the effects of 1 day and 10 days of cholesterol feeding on the nuclear receptors, FXR and LXRá in NZW rabbits. Changes in hepatic mRNA levels of FXR target genes (SHP, BSEP and CYP8B) and LXRá target genes (ABCA1 and CETP) were measured and served as activation markers for hepatic FXR and LXRá. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, levels of SHP, BSEP and CYP8B mRNAs were unchanged indicating that FXR activation remained constant. In contrast, the levels of LXRá target gene mRNAs, ABCA1 and CETP, increased 5-fold (p<0.01) and 2.3-fold (p<0.05) respectively associated with significant increases in hepatic concentrations of activating ligands (oxysterols) for LXRá. Activity and mRNA levels of CYP7A1, the target gene of both FXR and LXRá increased 2.4 (p<0.01) and 2.2 times (p<0.05) respectively. After 10 days of cholesterol feeding, the bile acid pool size and hepatic bile acid flux increased nearly 2-fold. SHP mRNA levels increased 4.1-fold (p<0.05) while CYP8B mRNA, a negatively regulated target gene of FXR, declined 64% (p<0.01). ABCA1 mRNA levels rose 8-fold (p<0.001) and CETP mRNA remained elevated. Activity and mRNA levels of CYP7A1 decreased 60% (p<0.001) and 90% (p<0.001) respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size nor change FXR activation while LXRá was activated highly secondary to increased formation of hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool and flux increased about 2 times which activated FXR strongly and inhibited CYP7A1 despite continued activation of LXRá. Thus, in rabbits, when FXR and LXRá are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXRá to suppress CYP7A1 mRNA expression.

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Farnesoid X receptor-mediated downregulation of CYP7A1 dominates LXR in long-term cholesterol-fed NZW rabbits

Farnesoid X receptor-mediated downregulation of CYP7A1 dominates LXR $alpha$ in long-term cholesterol-fed NZW rabbits