Restoration of Wnt/β-catenin signaling attenuates alcoholic liver disease progression in a rat model.
OBJECTIVE
Alcoholic liver disease (ALD) is characterized by the development of fatty liver, alcoholic hepatitis, fibrosis and cirrhosis. However, the underlying mechanism(s) associated with progression remains elusive. Pro-inflammatory cytokines have been implicated in ALD progression due to pro-apoptotic effects on hepatocytes. Wnt/β-catenin signaling recently has been shown to promote inflammation and apoptosis, suggesting that activation of this signaling pathway may modulate ALD progression. The current study was designed to test whether pharmacological activation of Wnt/β-catenin signaling altered ALD development and progression in a rat model.


METHODS
Adult male Long Evans rats were fed with isocaloric liquid diets containing 0% or 37% ethanol for 8 weeks, and also treated with Wnt agonist during the last 3 weeks of the feeding regimen. Liver and blood samples were subjected to histology, TUNEL assay, immunoblot analysis, real-time quantitative PCR, and alanine transaminase (ALT) assay.


RESULTS
Wnt/β-catenin signaling was negatively correlated with Foxo3A expression and reduced steatosis, cellular injury and apoptosis in ALD rats. Mutation experiments demonstrated that Foxo3A was critical for modulating these effects. Activation of Wnt/β-catenin signaling suppressed Foxo3A-induced apoptosis through upregulation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, pharmacological restoration of Wnt/β-catenin signaling reduced ALD progression in vivo.


CONCLUSIONS
Wnt/β-catenin signaling plays a protective role in ALD progression via antagonizing Foxo3A-induced apoptosis, and activation of the Wnt/β-catenin signaling cascade attenuates ALD progression.
Liver Research Center, Division of Gastroenterology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Chiung-Kuei
CK
Huang
Liver Research Center, Division of Gastroenterology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Tunan
T
Yu
Departments of Medicine and Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Suzanne M
SM
de la Monte
Liver Research Center, Division of Gastroenterology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Jack R
JR
Wands
Liver Research Center, Division of Gastroenterology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Zoltan
Z
Derdak
Liver Research Center, Division of Gastroenterology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Electronic address: Miran_Kim@brown.edu.
Miran
M
Kim
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D015151:Immunoblotting; D007150:Immunohistochemistry; D008108:Liver Diseases, Alcoholic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D051176:beta Catenin; D004247:DNA
Alcoholic liver disease; Apoptosis; Foxo3A; SGK1; Wnt