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Zhang R, Nakao T, Luo J, et al. Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatol Commun. 2019;3(12):1642-1655doi: 10.1002/hep4.1430.
Zhang, R., Nakao, T., Luo, J., Xue, Y., Cornuet, P., Oertel, M., Kosar, K., Singh, S., & Nejak-Bowen, K. (2019). Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatology communications, 3(12), 1642-1655. https://doi.org/10.1002/hep4.1430
Zhang, Rong, et al. "Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation." Hepatology communications vol. 3,12 (2019): 1642-1655. doi: https://doi.org/10.1002/hep4.1430
Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, Singh S, Nejak-Bowen K. Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatol Commun. 2019 Oct 14;3(12):1642-1655. doi: 10.1002/hep4.1430. eCollection 2019 Dec. PMID: 31832572; PMCID: PMC6887668.
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Hepatol Commun. 2019 Oct 14;3(12):1642-1655. doi: 10.1002/hep4.1430. eCollection 2019 Dec.

Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation.

Hepatology communications

Rong Zhang, Toshimasa Nakao, Jing Luo, Yuhua Xue, Pamela Cornuet, Michael Oertel, Karis Kosar, Sucha Singh, Kari Nejak-Bowen

Affiliations

  1. Department of Pathology University of Pittsburgh Pittsburgh PA.
  2. Department of Drug Discovery Medicine Kyoto Prefectural University of Medicine Kyoto Japan.
  3. Department of Surgery University of Pittsburgh Pittsburgh PA.
  4. Pittsburgh Liver Research Center University of Pittsburgh Pittsburgh PA.

PMID: 31832572 PMCID: PMC6887668 DOI: 10.1002/hep4.1430

Abstract

We have recently shown that loss of β-catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/β-catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β-catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β-catenin is intact (low-density lipoprotein receptor-related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β-catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild-type (WT) mice. Notably, the FXR/β-catenin complex was maintained in DKO livers after BDL, coincident with significantly elevated hepatic BA levels. Similarly, TG mice did not display accelerated injury or increased mortality despite overexpression of β-catenin. There was no augmentation of FXR/β-catenin association in TG livers; this resulted in equivalent hepatic BAs in WT and TG mice after BDL. Finally, we analyzed the effect of BDL on β-catenin activity and identified an increase in periportal cytoplasmic stabilization and association with T-cell factor 4 that correlated with increased expression of distinct downstream target genes.

© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

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