title: Ursodeoxycholic acid influences the expression of p27kip1 but not FoxO1 in patients with non-cirrhotic primary biliary cirrhosis.
abstract: BACKGROUND
  Enhanced expression of cell cycle inhibitor p27(kip1) suppresses cell proliferation. Ursodeoxycholic acid (UDCA) delays progression of primary biliary cirrhosis (PBC) but its effect on p27(kip1) expression is uncertain.
  
  
  OBJECTIVE
  To analyze the expression of p27(kip1) and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway.
  
  
  METHODS
  The examined human tissue included explanted livers from patients with cirrhotic PBC (n = 23), primary sclerosing cholangitis (PSC; n = 9), alcoholic liver disease (ALD; n = 9), and routine liver biopsies from patients with non-cirrhotic PBC (n = 26). Healthy liver samples served as controls (n = 19). Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot.
  
  
  RESULTS
  p27(kip1) expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls). FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P < 0.05 versus control). UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27(kip1) mRNA.
  
  
  CONCLUSIONS
  PBC progression is characterized by a FoxO1-independent increase of p27(kip1) expression. In early PBC, UDCA may enhance liver regeneration via p27(kip1)-dependent mechanism.
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Aleja Powstancow Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milkiewicz
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Aleja Powstancow Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Kopycińska
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Aleja Powstancow Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kempińska-Podhorodecka
authors.affiliation: Angiogenesis Research Group, Faculty of Health, York University, Toronto, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Haas
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Institute of Liver Studies, King's College London Medical School at King's College London Hospital, London SE5 9RS, UK.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Bogdanos
authors.affiliation: Liver Unit, University of Birmingham, Birmingham B15 2TH, UK.
authors.forename: Elwyn
authors.initials: E
authors.lastname: Elias
authors.affiliation: Liver Research Laboratories, Pomeranian Medical University, 70-111 Szczecin, Poland ; Department of General, Transplant and Liver Surgery, Liver and Internal Medicine Unit, Warsaw Medical University, 02-092 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: C436291:CDKN1B protein, human; D002756:Cholagogues and Choleretics; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014580:Ursodeoxycholic Acid
references.citation: J Clin Invest. 1998 Jun 15;101(12):2790-9
references.pmid: 9637713
references.citation: Cell. 1996 May 31;85(5):707-20
references.pmid: 8646779
references.citation: Gastroenterology. 2007 Apr;132(4):1434-46
references.pmid: 17408630
references.citation: Gene. 2000 Apr 18;247(1-2):1-15
references.pmid: 10773440
references.citation: J Cell Sci. 2007 Aug 1;120(Pt 15):2479-87
references.pmid: 17646672
references.citation: Mol Cancer Ther. 2008 May;7(5):1164-75
references.pmid: 18483304
references.citation: Oncogene. 2008 Apr 7;27(16):2289-99
references.pmid: 18391971
references.citation: Hepatology. 1999 Mar;29(3):644-7
references.pmid: 10051462
references.citation: N Engl J Med. 2007 Oct 11;357(15):1524-9
references.pmid: 17928600
references.citation: Trends Cell Biol. 2003 Feb;13(2):65-70
references.pmid: 12559756
references.citation: Cell Stem Cell. 2007 Aug 16;1(2):140-52
references.pmid: 18371346
references.citation: Gastroenterology. 2010 Nov;139(5):1481-96
references.pmid: 20849855
references.citation: Nat Immunol. 2008 Dec;9(12):1388-98
references.pmid: 18978794
references.citation: Cell. 2007 Jan 26;128(2):309-23
references.pmid: 17254969
references.citation: J Biol Chem. 2007 Sep 14;282(37):27141-27154
references.pmid: 17626006
references.citation: Am J Pathol. 2011 Feb;178(2):935-44
references.pmid: 21281824
references.citation: J Biol Chem. 2009 Aug 28;284(35):23204-16
references.pmid: 19574223
references.citation: Am J Pathol. 1999 Nov;155(5):1511-8
references.pmid: 10550307
references.citation: Nature. 2000 Apr 13;404(6779):782-7
references.pmid: 10783894
references.citation: J Biol Chem. 2002 Nov 15;277(46):44310-6
references.pmid: 12221098
references.citation: Ann N Y Acad Sci. 2012 Jan;1247:46-55
references.pmid: 22236474
references.citation: Int J Cancer. 2006 Jun 1;118(11):2750-7
references.pmid: 16385573
references.citation: Hepatology. 2010 Sep;52(3):987-98
references.pmid: 20568301
references.citation: Gastroenterology. 2008 Oct;135(4):1044-7
references.pmid: 18773895
references.citation: Mol Cell Biol. 2000 Dec;20(24):9138-48
references.pmid: 11094066
references.citation: Gastroenterology. 2003 Apr;124(4):889-93
references.pmid: 12671884
references.citation: Virchows Arch. 1997 Aug;431(2):119-24
references.pmid: 9293893
references.citation: J Immunol. 2002 May 15;168(10):5024-31
references.pmid: 11994454
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Jul;285(1):G115-27
references.pmid: 12646420
references.citation: Ann Surg Oncol. 2009 Feb;16(2):395-403
references.pmid: 19034576
references.citation: Hepatology. 2003 Jul;38(1):203-9
references.pmid: 12830003
references.citation: PLoS One. 2012;7(12):e52136
references.pmid: 23251696