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      Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7.

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          Abstract

          Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as hepatocyte growth factor (HGF), which restrains hepatic injury and facilitates reversibility of fibrotic reaction in response to an acute insult. Chronic liver injury and sustained inflammation cause progressive fibrosis and, ultimately, organ dysfunction. The mechanisms tipping the balance from restoration to progressive liver tissue scarring are not well understood. In the present study, we identify a mechanism in which the tumor-suppressor gene, cylindromatosis (CYLD), confers protection from hepatocellular injury and fibrosis. Mice lacking CYLD (CYLD-/-) were highly susceptible to hepatocellular damage, inflammation, and fibrosis and revealed significantly lower hepatic HGF levels, compared to wild-type (WT) animals. Exogenous application of HGF rescued the liver injury phenotype of CYLD-/- mice. In the absence of CYLD, gene transcription of HGF in hepatic stellate cells was repressed through binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In WT cells, CYLD removed HDAC7 from the HGF promoter and induced HGF expression. Of note, this interaction occurred independently of the deubiquitinating activity of CYLD.

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          Author and article information

          Journal
          Hepatology
          Hepatology (Baltimore, Md.)
          Wiley-Blackwell
          1527-3350
          0270-9139
          Sep 2014
          : 60
          : 3
          Affiliations
          [1 ] Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
          Article
          10.1002/hep.27209
          24811579

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