Pregnane X Receptor Activators Inhibit Human Hepatic Stellate Cell Transdifferentiation In Vitro (2006)

Author(s): Haughton EL, Tucker SJ, Marek CJ, Durward E, Leel V, Bascal Z, Monaghan T, Koruth M, Collie-Duguid E, Mann DA, Trim JE, Wright MC

    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 beta1, 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 beta1 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.

      • Date: 08-07-2006
      • Journal: Gastroenterology
      • Volume: 131
      • Issue: 1
      • Pages: 194-209
      • Publisher: WB Saunders Co.
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: Blotting, Western Carcinoma, Hepatocellular/drug therapy/*pathology Cell Differentiation/*drug effects Cell Proliferation/drug effects Comparative Study Enzyme Inhibitors/therapeutic use *Gene Expression Regulation, Neoplastic Hepatocytes/drug effects/pathology Humans In Vitro Liver Neoplasms/drug therapy/*pathology RNA, Neoplasm/*genetics Receptors, Cytoplasmic and Nuclear/drug effects/*genetics Receptors, Steroid/drug effects/*genetics Research Support, Non-U.S. Gov't Reverse Transcriptase Polymerase Chain Reaction Rifampin/*pharmacology Tumor Cells, Cultured


      Professor Derek Mann
      Prof of Hepatology

      Professor Matthew Wright
      Professor of Toxicology