Document Detail

Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis.
MedLine Citation:
PMID:  23295054     Owner:  NLM     Status:  In-Data-Review    
BACKGROUND/AIMS: Impaired regulation of apoptosis has been suggested to play a role in the pathogenesis of Primary Biliary Cirrhosis (PBC). In this study, we analysed a signalling pathway that comprises the transcription factor FoxO3a and its downstream target Bim, a Bcl-2 interacting mediator of apoptosis.
MATERIALS & METHODS: The tissues examined included livers explanted from patients with cirrhotic PBC, primary sclerosing cholangitis (PSC), alcoholic liver disease (ALD) and liver biopsies from patients with non-cirrhotic PBC. Large margin resections of hepatocellular carcinoma were used as controls.
RESULTS: Expression of FoxO3a and Bim mRNA was significantly enhanced in both non-cirrhotic and end-stage PBC (2.2-fold and 4.3-fold increases, respectively), but not in the other disorders. Similarly, FOXO3a protein level was increased in end-stage PBC (P < 0.05 vs. control). A significant increase in Bim mRNA in non-cirrhotic and cirrhotic PBC was observed (2.2-fold and 8.2-fold respectively). In addition, the most pro-apoptotic isoform of Bim dominated in livers of PBC patients (2.5- fold increase vs. control; P < 0.05). Enhanced FoxO3a and Bim expression was associated with a substantial activation of caspase-3 in PBC (2-fold increase vs. controls; P < 0.0001), whereas it was decreased in both ALD and PSC (46% and 67% reductions respectively). The relationship between FoxO3a and Bim was further investigated in the livers of FoxO-deficient mice. The somatic deletion of FoxO3a caused a significant decrease in Bim, but not caspase-3 protein expression confirming the crucial role of FoxO3a in induction of Bim gene transcription.
CONCLUSIONS: Our results imply that the FoxO3/Bim signalling pathway can be of importance in the livers of patients with PBC.
Justyna Kopycinska; Agnieszka Kempińska-Podhorodecka; Tara Haas; Elwyn Elias; Ronald A Depinho; Jihye Paik; Piotr Milkiewicz; Malgorzata Milkiewicz
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Liver international : official journal of the International Association for the Study of the Liver     Volume:  33     ISSN:  1478-3231     ISO Abbreviation:  Liver Int.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-08     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101160857     Medline TA:  Liver Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  231-8     Citation Subset:  IM    
Copyright Information:
© 2012 John Wiley & Sons A/S.
Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland.
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