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Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes.

Hepatology. 2007 Feb;45(2):433-44. doi:10.1002/hep.21456
Vesna S Stanulović 1 , Irene Kyrmizi , Marianna Kruithof-de Julio , Maarten Hoogenkamp , Jacqueline L M Vermeulen , Jan M Ruijter , Iannis Talianidis , Theodorus B M Hakvoort , Wouter H Lamers
Vesna S Stanulović 1 , Irene Kyrmizi , Marianna Kruithof-de Julio , Maarten Hoogenkamp , Jacqueline L M Vermeulen , Jan M Ruijter , Iannis Talianidis , Theodorus B M Hakvoort , Wouter H Lamers
+ et al

[No authors listed]

Author information
  • 1 AMC Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

摘要


UNLABELLED:In liver, most genes are expressed with a porto-central gradient. The transcription factor hepatic nuclear-factor4alpha (HNF4alpha) is associated with 12% of the genes in adult liver, but its involvement in zonation of gene expression has not been investigated. A putative HNF4alpha-response element in the upstream enhancer of glutamine synthetase (GS), an exclusively pericentral enzyme, was protected against DNase-I and interacted with a protein that is recognized by HNF4alpha-specific antiserum. Chromatin-immunoprecipitation assays of HNF4alpha-deficient (H4LivKO) and control (H4Flox) livers with HNF4alpha antiserum precipitated the GS upstream enhancer DNA only from H4Flox liver. Identical results were obtained with a histone-deacetylasel (HDAC1) antibody, but antibodies against HDAC3, SMRT and SHP did not precipitate the GS upstream enhancer. In H4Flox liver, GS, ornithine aminotransferase (OAT) and thyroid hormone-receptor beta1 (TRbeta1) were exclusively expressed in pericentral hepatocytes. In H4LivKO liver, this pericentral expression remained unaffected, but the genes were additionally expressed in the periportal hepatocytes, albeit at a lower level. The expression of the periportal enzyme phosphoenolpyruvate carboxykinase had declined in HNF4alpha-deficient hepatocytes. GS-negative cells, which were present as single, large hepatocytes or as groups of small cells near portal veins, did express HNF4alpha. Clusters of very small GS- and HNF4alpha-negative, and PCNA- and OV6-positive cells near portal veins were contiguous with streaks of brightly HNF4alpha-positive, OV6-, PCNA-, and PEPCK-dim cells. CONCLUSION:Our findings show that HNF4alpha suppresses the expression of pericentral proteins in periportal hepatocytes, possibly via a HDAC1-mediated mechanism. Furthermore, we show that HNF4alpha deficiency induces foci of regenerating hepatocytes.