title: Changes of activity and isoforms of alkaline sphingomyelinase (nucleotide pyrophosphatase phosphodiesterase 7) in bile from patients undergoing endoscopic retrograde cholangiopancreatography.
abstract: BACKGROUND
  Alkaline sphingomyelinase (NPP7) is an ecto-enzyme expressed in intestinal mucosa, which hydrolyses sphingomyelin (SM) to ceramide and inactivates platelet activating factor. It is also expressed in human liver and released in the bile. The enzyme may have anti-tumour and anti-inflammatory effects in colon and its levels are decreased in patients with colon cancer and ulcerative colitis. Active NPP7 is translated from a transcript of 1.4 kb, whereas an inactive form from a 1.2 kb mRNA was found in colon and liver cancer cell lines. While the roles of NPP7 in colon cancer have been intensively studied, less is known about the function and implications of NPP7 in the bile. The present study examines the changes of NPP7 in bile of patients with various hepatobiliary diseases.
  
  
  METHODS
  Bile samples were obtained at endoscopic retrograde cholangiopancreatography (ERCP) in 59 patients with gallstone, other benign disease, tumour, and primary sclerosing cholangitis (PSC). The NPP7 activity was determined. The appearance of the 1.4 and 1.2 kb products in the bile was examined by Western blot. The results were correlated to the diseases and also plasma bilirubin and alkaline phosphatase.
  
  
  RESULTS
  NPP7 activity in the tumour group was significantly lower than in the gallstone group (p < 0.05). The activity in the tumour plus PSC group was also lower than in gallstone plus other benign disease group (p < 0.05). Within the tumour group NPP7 activity was lowest in cholangiocarcinoma patients, being only 19% of that in gallstone patients. Bilirubin correlated inversely to NPP7 and was higher in the tumour than in the gallstone group. Western blot identified both the 1.4 kb and the 1.2 kb products in most bile samples. The density ratio for the 1.4/1.2 kb products correlated to NPP7 activity significantly. Two patients (one PSC and one cholangiocarcinoma) lacking NPP7 activity had only the 1.2 kb form in bile.
  
  
  CONCLUSIONS
  NPP7 activity and the ratio of 1.4/1.2 kb products in bile are significantly decreased in malignancy, particularly in cholangiocarcinoma. The implications of the finding in diagnosis of cholangiocarcinoma and 1.2 kb product in hepatobiliary diseases require further investigation.
authors.affiliation: Gastroenterology & Nutrition Laboratory, BMC, B11, Department of Clinical Sciences in Lund, University of Lund, S-22184 Lund, Sweden. Rui-dong.duan@med.lu.se.
authors.forename: Rui-Dong
authors.initials: RD
authors.lastname: Duan
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
authors.forename: Yajun
authors.initials: Y
authors.lastname: Cheng
authors.forename: Per
authors.initials: P
authors.lastname: Bergenzaun
authors.forename: Mats
authors.initials: M
authors.lastname: Hall
authors.forename: Erik
authors.initials: E
authors.lastname: Hertervig
authors.forename: Åke
authors.initials: Å
authors.lastname: Nilsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001646:Bile / Q000201:enzymology*; D001650:Bile Duct Neoplasms / Q000201:enzymology; D001653:Bile Ducts, Intrahepatic; D001661:Biliary Tract Neoplasms / Q000201:enzymology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D018281:Cholangiocarcinoma / Q000201:enzymology; D002760:Cholangiopancreatography, Endoscopic Retrograde; D015209:Cholangitis, Sclerosing / Q000201:enzymology; D042883:Choledocholithiasis / Q000201:enzymology; D002769:Cholelithiasis / Q000201:enzymology; D057075:Enzyme Assays; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes; D008113:Liver Neoplasms / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007527:Isoenzymes; C508908:ENPP7 protein, human; D013108:Sphingomyelin Phosphodiesterase
references.citation: Trends Biochem Sci. 2005 Oct;30(10):542-50
references.pmid: 16125936
references.citation: Am J Physiol. 1998 May;274(5):G891-900
references.pmid: 9612271
references.citation: Am J Clin Nutr. 2010 Mar;91(3):672-8
references.pmid: 20071649
references.citation: Dig Dis Sci. 1996 Sep;41(9):1801-6
references.pmid: 8794797
references.citation: Biochim Biophys Acta. 1996 Mar 29;1300(1):42-8
references.pmid: 8608160
references.citation: Cancer Res. 2004 Nov 1;64(21):7647-54
references.pmid: 15520162
references.citation: Biochem J. 2005 Feb 15;386(Pt 1):153-60
references.pmid: 15458386
references.citation: Best Pract Res Clin Gastroenterol. 2011 Dec;25(6):753-64
references.pmid: 22117640
references.citation: Dig Dis Sci. 2009 Jul;54(7):1440-8
references.pmid: 18989780
references.citation: Biochim Biophys Acta. 2006 Mar;1761(3):281-91
references.pmid: 16631405
references.citation: Mol Cell. 2013 Oct 24;52(2):193-205
references.pmid: 24055345
references.citation: Br J Cancer. 1999 Sep;81(2):232-6
references.pmid: 10496347
references.citation: J Lipid Res. 2011 Apr;52(4):771-81
references.pmid: 21177474
references.citation: Biochim Biophys Acta. 1995 Oct 26;1259(1):49-55
references.pmid: 7492615
references.citation: J Cancer Res Clin Oncol. 2003 Oct;129(10):577-82
references.pmid: 12920578
references.citation: J Biol Chem. 2003 Oct 3;278(40):38528-36
references.pmid: 12885774
references.citation: Inflamm Bowel Dis. 2002 Jul;8(4):258-63
references.pmid: 12131609
references.citation: Biochem J. 2006 Feb 15;394(Pt 1):299-308
references.pmid: 16255717
references.citation: J Lipid Res. 2006 Jan;47(1):154-71
references.pmid: 16251722
references.citation: Best Pract Res Clin Gastroenterol. 2013 Aug;27(4):531-42
references.pmid: 24090940
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):856-62
references.pmid: 15824156
references.citation: Br J Cancer. 2007 Nov 19;97(10):1441-8
references.pmid: 17923876
references.citation: Cancer. 1997 Feb 1;79(3):448-53
references.pmid: 9028353
references.citation: J Nutr Biochem. 2000 May;11(5):244-9
references.pmid: 10876096
references.citation: Am J Physiol. 1992 Nov;263(5 Pt 1):G587-92
references.pmid: 1443133
references.citation: Hepatology. 1997 Oct;26(4):823-30
references.pmid: 9328299
references.citation: Biochim Biophys Acta. 1969 Mar 4;176(2):339-47
references.pmid: 5775951
references.citation: Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
references.pmid: 18216770
references.citation: Lancet. 2005 Oct 8;366(9493):1303-14
references.pmid: 16214602
references.citation: Nat Genet. 2002 Jan;30(1):13-9
references.pmid: 11753382
references.citation: Carcinogenesis. 2004 Aug;25(8):1327-33
references.pmid: 15016655
references.citation: Curr Gastroenterol Rep. 2006 Feb;8(1):30-7
references.pmid: 16510032
references.citation: Methods Enzymol. 2000;311:276-86
references.pmid: 10563333
references.citation: Dig Dis Sci. 1998 Jan;43(1):26-32
references.pmid: 9508530
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Nov;287(5):G967-73
references.pmid: 15205117
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10231-3
references.pmid: 12149519
references.citation: Biochimie. 2010 Jun;92(6):692-7
references.pmid: 20167241