Liver fibrosis is a wound healing response to chronic hepatocellular damage. The activated pregnane X receptor has been shown to exert an anti-fibrogenic effect in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of the human pregnane X receptor on hepatic stellate cell trans-differentiation to a pro-fibrogenic phenotype in vitro. Primary hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiated into a pro-fibrogenic phenotype with increased expression of extracellular matrix components, cytokines and chemokines. Here we have demonstrated that the pregnane X receptor was expressed in primary cultures of hepatic stellate cells as well as a hepatic stellate cell line at the level of mRNA and protein, and was transcriptionally functional as determined by increased ER6-dependent reporter gene expression. Short term treatment of hepatic stellate cells with pregnane X receptor ligands such as rifampicin resulted in an increase in interleukin-6 secretion as well as an inhibition in DNA synthesis. Interleukin-6 promoter studies in primary hepatic stellates and the LX-2 hepatic stellate cell line suggested that the activated protein-1 site and nuclear factor interleukin-6 sites were required for pregnane X receptor-mediated regulation. Chronic ligand treatment over several weeks resulted in reduced proliferation and trans-differentiation of hepatic stellate cells with no obvious effect on the rate of apoptosis. We therefore conclude that the pregnane X receptor is transcriptionally active in human hepatic stellate cells and that activators inhibit the trans-differentiation and proliferation in culture. The pregnane X receptor may therefore be an effective target for anti-fibrotic therapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590954 |
| Date | January 2007 |
| Creators | Haughton, Emma Louise |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU223277 |
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