| Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis. | |
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MedLine Citation:
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PMID: 23295054 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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. |
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Authors:
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Justyna Kopycinska; Agnieszka Kempińska-Podhorodecka; Tara Haas; Elwyn Elias; Ronald A Depinho; Jihye Paik; Piotr Milkiewicz; Malgorzata Milkiewicz |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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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:
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Created Date: 2013-01-08 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101160857 Medline TA: Liver Int Country: United States |
Other Details:
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Languages: eng Pagination: 231-8 Citation Subset: IM |
Copyright Information:
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© 2012 John Wiley & Sons A/S. |
Affiliation:
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Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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