caa a22 4500 445884991 CHVBK 20180317145556.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00011-010-0306-1 doi (NATIONALLICENCE)springer-10.1007/s00011-010-0306-1 SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-γ by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts [Elektronische Daten] [Barbara Renga, Andrea Mencarelli, Marco Migliorati, Sabrina Cipriani, Claudio D'Amore, Eleonora Distrutti, Stefano Fiorucci] Objective: The regulation of hepatic stellate cells (HSCs) by bacterial lipopolysaccharide (LPS) represents a recently-discovered and novel mechanism for hepatic injury and fibrosis. Stimulation of HSCs with LPS results in a rapid and marked induction of interleukin (IL)1β, IL6 and tumor necrosis factor α. These events lead to the development of the activated phenotype in the HSCs associated with fibrosis and inflammation in the injured liver. We have previously demonstrated that farnesoid X receptor (FXR) activation increases transcription of rat peroxisome proliferator-activated receptor-γ (PPARγ) gene in HSCs. We aimed at evaluating the molecular mechanism of the transcriptional regulation of the PPARγ gene by FXR. Methods: Real-time PCR, ELISA, transactivations, EMSA and ChIP experiments were performed in HSC-T6 cells, in primary HSCs, in HEK293T cells and in CCl4-treated rats. Results: In vivo and in vitro activation of FXR downregulates cytokines and collagen(α)1 while inducing PPARγ and small heterodimer partner (SHP). NUBIScan analysis of rat PPARγ promoter revealed the presence of a putative FXR response element. Cotransfection with FXR/retinoic acid receptor significantly enhanced chenodeoxycholic acid-induced luciferase activity. EMSA experiments demonstrated that FXR was able to bind to an inverted repeat-1 sequence and ChIP experiments confirmed that FXR is recruited on the PPARγ promoter. Conclusion: The present study provides a molecular basis for the physiological cross-talk between FXR and PPARγ pathways in HSCs. Springer Basel AG, 2011 Hepatic stellate cells nationallicence Farnesoid X receptor nationallicence Peroxisome proliferator-activated receptor-γ nationallicence Liver inflammation nationallicence HSC-T6 cells nationallicence FXR : Farnesoid X receptor nationallicence SHP : Small heterodimer partner nationallicence PPARγ : Peroxisome proliferator-activated receptor-γ nationallicence HSCs : Hepatic stellate cells nationallicence LPS : Lipopolysaccharide nationallicence IL1β : Interleukin 1 beta nationallicence IL6 : Interleukin 6 nationallicence TNFα : Tumor necrosis factor alpha nationallicence EMSA : Electrophoretic mobility shift assay nationallicence ChIP : Chromatin immunoprecipitation nationallicence IR1 : Inverted repeat-1 nationallicence CDCA : Chenodeoxycholic acid nationallicence Renga Barbara Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut Mencarelli Andrea Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut Migliorati Marco Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut Cipriani Sabrina Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut D'Amore Claudio Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut Distrutti Eleonora Hospital Saint Mary of Mercy, 06122, Perugia, Italy aut Fiorucci Stefano Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut Inflammation Research SP Birkhäuser Verlag Basel 60/6(2011-06-01), 577-587 1023-3830 60:6<577 2011 60 11 https://doi.org/10.1007/s00011-010-0306-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00011-010-0306-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Renga Barbara Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- Mencarelli Andrea Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- Migliorati Marco Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- Cipriani Sabrina Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- D'Amore Claudio Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- Distrutti Eleonora Hospital Saint Mary of Mercy, 06122, Perugia, Italy aut NATIONALLICENCE 700 1- Fiorucci Stefano Department of Experimental and Clinical Medicine, University of Perugia, Street E. dal Pozzo, 06122, Perugia, Italy aut NATIONALLICENCE 773 0- Inflammation Research SP Birkhäuser Verlag Basel 60/6(2011-06-01), 577-587 1023-3830 60:6<577 2011 60 11 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer