Abstract
Production of bile by the liver is crucial for the absorption of lipophilic nutrients. Dysregulation of bile acid homeostasis can lead to cholestatic liver disease and endoplasmic reticulum (ER) stress. We show by global location analysis ('ChIP-on-chip') and cell type–specific gene ablation that the winged helix transcription factor Foxa2 is required for normal bile acid homeostasis. As suggested by the location analysis, deletion of Foxa2 in hepatocytes in mice using the Cre-lox system leads to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice are strikingly sensitive to a diet containing cholic acid, which results in toxic accumulation of hepatic bile salts, ER stress and liver injury. In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury.
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Acknowledgements
We thank D.D. Moore for advice on the cholic acid diet; J.A. Whittsett (Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine) for providing rabbit polyclonal antibodies to Foxa2; K. Ma and L.E. Greenbaum for critical reading of the manuscript; D. Ye, A. Arsenlis, G. Tuteja and N. Gao for contributions to this project; and E. Rand, and the Fred and Suzanne Biesecker Pediatric Liver Center for providing pediatric liver samples. We are grateful to S. Hammani and E. Helmbrecht for care of the mice. Our studies were assisted by the University of Pennsylvania Diabetes Center (P30DK19525). This work was supported by grants DK-049210 and DK-056947 to K.H.K. I.M.B. was supported by training grant T32-HG000046 and a Penn Genomics Institute Graduate Fellowship.
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I.M.B. developed the project, performed most of the experiments and data analysis and wrote the draft of the manuscript. N.E.R. and P.W. performed some of the experiments and data analysis. E.E.F. and J.R.F. contributed to the human tissue studies. K.H.K. directed the project and reviewed and edited the manuscript.
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Bochkis, I., Rubins, N., White, P. et al. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med 14, 828–836 (2008). https://doi.org/10.1038/nm.1853
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DOI: https://doi.org/10.1038/nm.1853
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