title: Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Kopycinska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kempińska-Podhorodecka
authors.forename: Tara
authors.initials: T
authors.lastname: Haas
authors.forename: Elwyn
authors.initials: E
authors.lastname: Elias
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Jihye
authors.initials: J
authors.lastname: Paik
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milkiewicz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D015209:Cholangitis, Sclerosing / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism / Q000503:physiopathology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053148:Caspase 3