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Ectonucleotidase NTPDase2 Is Selectively Down-Regulated in Biliary Cirrhosis
  1. Jonathan A. Dranoff,
  2. Emma A. Kruglov,
  3. Joahd Toure,
  4. Norbert Braun,
  5. Herbert Zimmermann,
  6. Dhanpat Jain,
  7. Aileen F. Knowles,
  8. Jean Sévigny
  1. From the Section of Digestive Diseases and Yale Liver Center (J.A.D., E.A.K., J.T.) and Department of Pathology (D.J.), Yale University School of Medicine, New Haven, CT; AK Neurochemie, Zoologisches Institut (N.B., H.Z.), J.W. Goethe-Universität, Frankfurt, Germany; Department of Biology (A.F.K.), San Diego State University, San Diego, CA; Department of Anatomy and Physiology (J.S.), Université Laval, Quebec, PQ.
  2. Supported by National Institutes of Health (NIH) grant DK-02379 and a research award from the Patterson Trust (to J.A.D.), Deutsche Forschungsgemeinschaft grant number SFB 269, A4 (to N.B. and H.Z.), and the Yale Liver Center NIH grant DK-34989.
  3. Address correspondence to: Dr. Jonathan A. Dranoff, Yale University School of Medicine, The Anlyan Center, Rm S223-B, One Gilbert Street, New Haven, CT 06520; e-mail: jonathan.dranoff{at}yale.edu.

Abstract

Background Portal fibroblasts are newly identified, potentially fibrogenic liver cells that are distinct from hepatic stellate cells. The ectonucleotidase* nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is restricted to portal fibroblasts in the normal liver. However, the fate of NTPDase2 after bile duct ligation (BDL) is unknown.

* Extracellular enzymes that mediate the degradation of adenosine triphosphate (ATP) and other nucleotides.

Aims The aim of this study was to assess the effect of experimental rat and disease-mediated human biliary cirrhosis on NTP-Dase2 expression in the liver.

Methods Cirrhosis was induced in experimental rats via BDL and carbon tetrachloride (CCl4) administration. Archived human liver biopsy specimens from normal liver, primary biliary cirrhosis, or hepatitis C cirrhosis were examined. Changes in expression of NTPDase2 were determined using confocal immunofluorescence, immunoblot, and real-time polymerase chain reaction.

Results Confocal immunofluorescence demonstrated a decrease in NTPDase2 expression after BDL. Immunoblot and real-time polymerase chain reaction demonstrated a decrease in NTPDase2 expression by portal fibroblasts after BDL. No decrease in NTP-Dase2 protein was noted after CCl4 administration, and NTPDase2 messenger ribonucleic acid was markedly up-regulated after CCl4 administration. Confocal immunofluorescence demonstrated a shift of NTPDase2 expression from portal areas to central areas that colocalized with α-smooth muscle actin after CCl4 administration. In human biopsy specimens, NTPDase2 expression was lost in cirrhosis owing to primary biliary cirrhosis, whereas NTPDase2 expression was shifted to bridging fibrous bands in cirrhosis owing to hepatitis C.

Conclusions Loss of NTPDase2 is a common pathway in both rat and human manifestations of biliary cirrhosis. Conversely, in nonbiliary cirrhosis, NTPDase2 is shifted from the portal area to bridging fibrous bands. Elucidations of the mechanisms regulating NTP-Dase2 expression may lead to new therapeutic approaches to fibrotic liver disease.

Key Words
  • biliary cirrhosis
  • cholestasis
  • ecto-ATPase
  • ectonucleotidase
  • liver fibrosis

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