TY - JOUR
T1 - β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis
AU - Thompson, Michael D.
AU - Moghe, Akshata
AU - Cornuet, Pamela
AU - Marino, Rebecca
AU - Tian, Jianmin
AU - Wang, Pengcheng
AU - Ma, Xiaochao
AU - Abrams, Marc
AU - Locker, Joseph
AU - Monga, Satdarshan P.
AU - Nejak-Bowen, Kari
N1 - Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2018/3
Y1 - 2018/3
N2 - Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for β-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that β-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of β-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of β-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of β-catenin expression during cholestatic injury reduces β-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. Conclusion: We have identified an FXR/β-catenin interaction whose modulation through β-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955–971).
AB - Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for β-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that β-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of β-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of β-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of β-catenin expression during cholestatic injury reduces β-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. Conclusion: We have identified an FXR/β-catenin interaction whose modulation through β-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955–971).
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U2 - 10.1002/hep.29371
DO - 10.1002/hep.29371
M3 - Article
C2 - 28714273
AN - SCOPUS:85041080497
SN - 0270-9139
VL - 67
SP - 955
EP - 971
JO - Hepatology
JF - Hepatology
IS - 3
ER -