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J. Lipid Res.
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Journal of Lipid Research, Vol. 43, 45-50, January 2002
Copyright © 2002 by Lipid Research, Inc.

Removal of the bile acid pool upregulates cholesterol 7{alpha}-hydroxylase by deactivating FXR in rabbits

Guorong Xua,b, Lu-xing Panb, Sandra K. Ericksonc, Barry M. Formand, Benjamin L. Shneidere, M. Ananthanarayanane, Xiaogui Lib, Sarah Sheferb, N. Balasubramaniane, Lin Mae, Hitoshi Asaokab, Steven R. Learc, Lien B. Nguyenb, Isabelle Dussaultd, Frederick J. Suchye, G. Stephen Tinta,b, and Gerald Salena,b
a Medical Service, Veterans Affairs Medical Center, East Orange, NJ 07018
b Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
c Department of Medicine, UCSF and VA Medical Center, San Francisco, CA 94121
d Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010
e Department of Pediatrics, Mt. Sinai School of Medicine, New York, NY 10029

Correspondence to: Guorong Xu, at GI Lab (15A), VA Medical Center, 385 Tremont Avenue, East Orange, NJ 07018-1095., xugu{at}umdnj.edu (E-mail)

We investigated the role of the orphan nuclear receptor farnesoid X receptor (FXR) in the regulation of cholesterol 7{alpha}-hydroxylase (CYP7A1), using an in vivo rabbit model, in which the bile acid pool, which includes high affinity ligands for FXR, was eliminated. After 7 days of bile drainage, the enterohepatic bile acid pool, in both New Zealand White and Watanabe heritable hyperlipidemic rabbits, was depleted. CYP7A1 activity and mRNA levels increased while FXR was deactivated as indicated by reduced FXR protein and changes in the expression of target genes that served as surrogate markers of FXR activation in the liver and ileum, respectively. Hepatic bile salt export pump mRNA levels and ileal bile acid-binding protein decreased while sterol 12{alpha}-hydroxylase and sodium/taurocholate cotransporting polypeptide mRNA levels increased in the liver. In addition, hepatic FXR mRNA levels decreased significantly.

The data, taken together, indicate that FXR was deactivated when the bile acid pool was depleted such that CYP7A1 was upregulated. Further, lack of the high affinity ligand supply was associated with downregulation of hepatic FXR mRNA levels. — Xu, G., L-x. Pan, S. K. Erickson, B. M. Forman, B. L. Shneider, M. Ananthanarayanan, X. Li, S. Shefer, N. Balasubramanian, L. Ma, H. Asaoka, S. R. Lear, L. B. Nguyen, I. Dussault, F. J. Suchy, G. S. Tint, and G. Salen. Removal of the bile acid pool upregulates cholesterol 7{alpha}-hydroxylase by deactivating FXR in rabbits. J. Lipid Res. 2002. 43: 45–50.

Supplementary key words: bile salt export pump, biosynthesis, farnesoid X receptor, ileal bile acid-binding protein, orphan nuclear receptor


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