Pregnane X Receptor Activators Inhibit Human Hepatic Stellate Cell Trans-Differentiation in Vitro

Emma Haughton, Steven John Tucker, Carylyn Marek, Elaine Durward, Valerie Hilda Marie Duncan Leel, Z. Bascal, T. Monaghan, M. Koruth, Elaina Susan Renata Collie-Duguid, D. A. Mann, J. E. Trim, Matthew Christopher Wright

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Abstract

Background & Aims: The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro. Methods: Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts. Results: The pregnane X receptor was expressed in primary cultures at the level of messenger RNA and protein and was activated by the ligand rifampicin as judged by increases in binding of proteins to the pregnane X receptor ER6 DNA response element and by increases in ER6-dependent reporter gene expression. Short-term treatment of hepatic stellate cells with rifampicin inhibited the expression of selected fibrosis-related genes (transforming growth factor beta 1, alpha-smooth muscle actin), proliferation-related genes, and WNT signaling-associated genes. There was also an increase in interleukin-6 secretion and an inhibition in DNA synthesis. Long-term treatment with rifampicin over several weeks reduced the proliferation and transdifferentiation of hepatic stellate cells. Small interfering RNA knockdown of the pregnane X receptor in a hepatic stellate cell line reduced the binding of proteins to the ER6 DNA response element and abrogated pregnane X receptor activator-dependent changes in transforming growth factor beta 1 expression, interleukin-6 secretion, and proliferation. Conclusions: The pregnane X receptor is transcriptionally functional in human hepatic stellate cells and activators inhibit transdifferentiation and proliferation. The pregnane X receptor may therefore be an effective target for antifibrotic therapy.

Original languageEnglish
Pages (from-to)194-209
Number of pages15
JournalGastroenterology
Volume131
Issue number1
DOIs
Publication statusPublished - Jul 2006

Keywords

  • INTERLEUKIN-6-DEFICIENT MICE
  • FIBROSIS
  • REGENERATION
  • MECHANISMS
  • EXPRESSION
  • METYRAPONE
  • GLIOTOXIN
  • LIGANDS
  • INJURY
  • CYP3A4

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