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Prevention of cholesterol gallstone disease by FXR agonists in a mouse model

Abstract

Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease.

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Figure 1: Biliary cholesterol crystallization, lipid profiles and gallbladder inflammation in lithogenic FXR−/− mice.
Figure 2: Gene expression in lithogenic FXR−/− mice.
Figure 3: Effects of FXR agonist on cholesterol crystallization and gallstone formation in susceptible wild-type (C57L) and FXR−/− mice.
Figure 4: Liver gene expression in cholesterol gallstone susceptible C57L and FXR−/− mice.
Figure 5: Model of increased susceptibility to cholesterol gallstone formation and its prevention by FXR agonists in lithogenic animals.

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Acknowledgements

The authors thank F. Gonzalez for supplying the FXR−/− mice used in these studies and T. Willson (GlaxoSmithKline) for supplying the synthetic FXR agonist GW4064; D. Russell, S. Kliewer, J. Repa, G. Palasciano, P. Portincasa, G. van Berge Henegouwen, K. van Erpecum and A. Hofmann for criticisms and discussions; C. Cummins, D. Jung, A. Liverman and X. Zhi from the Mango lab for contributing to the in vivo studies and S. Clark for expertise in the HPLC measurements of bile salts. D.J.M. is an investigator and A.M. is a research associate at the Howard Hughes Medical Institute (HHMI). This work was funded by HHMI, the Robert Welch Foundation (I-1275), and the National Institutes of Health (Atlas grant U19DK62434).

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Correspondence to David J Mangelsdorf.

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D.J.M. is a consultant for X-Ceptor Therapeutics, Inc.

Supplementary information

Supplementary Fig. 1

Gene expression in wild-type, Nr1h4−/− and C57L mice. (PDF 329 kb)

Supplementary Table 1 (PDF 8 kb)

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Moschetta, A., Bookout, A. & Mangelsdorf, D. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 10, 1352–1358 (2004). https://doi.org/10.1038/nm1138

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