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CYLD regulates HGF expression in hepatic stellate cells via interaction with HDAC7.

Rajeswara, Pannem Rao LU ; Dorn, Christoph; Hellerbrand, Claus and Massoumi, Ramin LU (2014) In Hepatology 60(3). p.1066-1081
Abstract
Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as the hepatocyte growth factor (HGF), which restrain hepatic injury and facilitate the reversibility of the 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... (More)
Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as the hepatocyte growth factor (HGF), which restrain hepatic injury and facilitate the reversibility of the 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 with wild-type 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 the binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In wildtype cells, CYLD removed HDAC7 from HGF promoter and induced HGF expression. Noteworthy, this interaction occurred independent of deubiquitinating activity of CYLD. Conclusions: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to the progression of liver disease. Thus, through the regulation of the HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis. (Hepatology 2014). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Hepatology
volume
60
issue
3
pages
1066 - 1081
publisher
John Wiley & Sons
external identifiers
  • pmid:24811579
  • wos:000341239200032
  • scopus:84906511146
ISSN
1527-3350
DOI
10.1002/hep.27209
language
English
LU publication?
yes
id
d1e08d96-1425-428f-940b-5f6631070b6b (old id 4455626)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24811579?dopt=Abstract
date added to LUP
2014-06-03 21:44:10
date last changed
2017-04-30 05:22:14
@article{d1e08d96-1425-428f-940b-5f6631070b6b,
  abstract     = {Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as the hepatocyte growth factor (HGF), which restrain hepatic injury and facilitate the reversibility of the 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 with wild-type 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 the binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In wildtype cells, CYLD removed HDAC7 from HGF promoter and induced HGF expression. Noteworthy, this interaction occurred independent of deubiquitinating activity of CYLD. Conclusions: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to the progression of liver disease. Thus, through the regulation of the HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis. (Hepatology 2014).},
  author       = {Rajeswara, Pannem Rao and Dorn, Christoph and Hellerbrand, Claus and Massoumi, Ramin},
  issn         = {1527-3350},
  language     = {eng},
  number       = {3},
  pages        = {1066--1081},
  publisher    = {John Wiley & Sons},
  series       = {Hepatology},
  title        = {CYLD regulates HGF expression in hepatic stellate cells via interaction with HDAC7.},
  url          = {http://dx.doi.org/10.1002/hep.27209},
  volume       = {60},
  year         = {2014},
}