2002•Journal of Lipid ResearchOpen access
Removal of the bile acid pool upregulates cholesterol 7α-hydroxylase by deactivating FXR in rabbits
Guorong Xu, Luxing Pan, Sandra K. Erickson, Barry M. Forman, Benjamin L. Shneider, Meenakshisundaram Ananthanarayanan, Xiaogui Li, Sarah Shefer, Niranjan Balasubramanian, Lin Ma, Hitoshi Asaoka, Steven R. Lear, Lien B. Nguyen, Isabelle Dussault, Frederick J. Suchy, G. Stephen Tint, Gerald Salen
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Abstract
We investigated the role of the orphan nuclear receptor farnesoid X receptor (FXR) in the regulation of cholesterol 7α-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 12α-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 7α-hydroxylase by deactivating FXR in rabbits. J. Lipid Res. 2002. 43: 45–50.