Saori Koh1, Tappei Takada, Ikuya Kukuu, Hiroshi Suzuki. 1. Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Abstract
PURPOSE: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a specific form of genetic cholestasis caused by functional defects in FIC1/ATP8B1. Although the way FIC1 deficiency leads to PFIC1 remains unclear, some reports suggest that the loss of FIC1 function results in decreased activity of the farnesoid X receptor (FXR) in PFIC1 patients. In this study, in order to elucidate the molecular mechanism of the pathogenesis of PFIC1, we constructed an experimental system for the evaluation of FIC1-mediated stimulatory effects on FXR activity. METHODS AND RESULTS: Luciferase assays revealed that FIC1 expression increased FXR-dependent transcription and that the effects of three PFIC1 mutants (G308V, T456M and D554N) were smaller than that of wild-type FIC1. In addition, the PFIC1 mutants could not locate to the plasma membrane even in the presence of CDC50A, which brings wild-type FIC1 to the plasma membrane. The results of coprecipitation assays suggested a defect in the ability of the PFIC1 mutants to interact with CDC50A. Furthermore, it was revealed that the expression of CDC50A elevated the FIC1-mediated transcriptional stimulation when coexpressed with wild-type FIC1, but not with mutated FIC1. CONCLUSIONS: These results suggest that the PFIC1 mutants have a lower stimulatory effect on FXR activity and cannot interact with CDC50A, which may lead to the development of the features of PFIC1.
PURPOSE: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a specific form of genetic cholestasis caused by functional defects in FIC1/ATP8B1. Although the way FIC1 deficiency leads to PFIC1 remains unclear, some reports suggest that the loss of FIC1 function results in decreased activity of the farnesoid X receptor (FXR) in PFIC1patients. In this study, in order to elucidate the molecular mechanism of the pathogenesis of PFIC1, we constructed an experimental system for the evaluation of FIC1-mediated stimulatory effects on FXR activity. METHODS AND RESULTS: Luciferase assays revealed that FIC1 expression increased FXR-dependent transcription and that the effects of three PFIC1 mutants (G308V, T456M and D554N) were smaller than that of wild-type FIC1. In addition, the PFIC1 mutants could not locate to the plasma membrane even in the presence of CDC50A, which brings wild-type FIC1 to the plasma membrane. The results of coprecipitation assays suggested a defect in the ability of the PFIC1 mutants to interact with CDC50A. Furthermore, it was revealed that the expression of CDC50A elevated the FIC1-mediated transcriptional stimulation when coexpressed with wild-type FIC1, but not with mutated FIC1. CONCLUSIONS: These results suggest that the PFIC1 mutants have a lower stimulatory effect on FXR activity and cannot interact with CDC50A, which may lead to the development of the features of PFIC1.
Authors: L A Denson; E Sturm; W Echevarria; T L Zimmerman; M Makishima; D J Mangelsdorf; S J Karpen Journal: Gastroenterology Date: 2001-07 Impact factor: 22.682
Authors: Tamara Frankenberg; Tamir Miloh; Frank Y Chen; Meena Ananthanarayanan; An-Qiang Sun; Natarajan Balasubramaniyan; Irwin Arias; Kenneth D R Setchell; Frederick J Suchy; Benjamin L Shneider Journal: Hepatology Date: 2008-12 Impact factor: 17.425
Authors: M Makishima; A Y Okamoto; J J Repa; H Tu; R M Learned; A Luk; M V Hull; K D Lustig; D J Mangelsdorf; B Shan Journal: Science Date: 1999-05-21 Impact factor: 47.728
Authors: Anuradha Rao; Jamie Haywood; Ann L Craddock; Martin G Belinsky; Gary D Kruh; Paul A Dawson Journal: Proc Natl Acad Sci U S A Date: 2008-02-21 Impact factor: 11.205
Authors: Coen C Paulusma; Dineke E Folmer; Kam S Ho-Mok; D Rudi de Waart; Petra M Hilarius; Arthur J Verhoeven; Ronald P J Oude Elferink Journal: Hepatology Date: 2008-01 Impact factor: 17.425
Authors: Ryan M Allen; Tyler J Marquart; Carolyn J Albert; Frederick J Suchy; David Q-H Wang; Meenakshisundaram Ananthanarayanan; David A Ford; Angel Baldán Journal: EMBO Mol Med Date: 2012-07-05 Impact factor: 12.137
Authors: Daan B E van Wessel; Richard J Thompson; Emmanuel Gonzales; Irena Jankowska; Benjamin L Shneider; Etienne Sokal; Tassos Grammatikopoulos; Agustina Kadaristiana; Emmanuel Jacquemin; Anne Spraul; Patryk Lipiński; Piotr Czubkowski; Nathalie Rock; Mohammad Shagrani; Dieter Broering; Talal Algoufi; Nejat Mazhar; Emanuele Nicastro; Deirdre Kelly; Gabriella Nebbia; Henrik Arnell; Björn Fischler; Jan B F Hulscher; Daniele Serranti; Cigdem Arikan; Dominique Debray; Florence Lacaille; Cristina Goncalves; Loreto Hierro; Gema Muñoz Bartolo; Yael Mozer-Glassberg; Amer Azaz; Jernej Brecelj; Antal Dezsőfi; Pier Luigi Calvo; Dorothee Krebs-Schmitt; Steffen Hartleif; Wendy L van der Woerd; Jian-She Wang; Li-Ting Li; Özlem Durmaz; Nanda Kerkar; Marianne Hørby Jørgensen; Ryan Fischer; Carolina Jimenez-Rivera; Seema Alam; Mara Cananzi; Noémie Laverdure; Cristina Targa Ferreira; Felipe Ordonez; Heng Wang; Valerie Sency; Kyung Mo Kim; Huey-Ling Chen; Elisa Carvalho; Alexandre Fabre; Jesus Quintero Bernabeu; Estella M Alonso; Ronald J Sokol; Frederick J Suchy; Kathleen M Loomes; Patrick J McKiernan; Philip Rosenthal; Yumirle Turmelle; Girish S Rao; Simon Horslen; Binita M Kamath; Maria Rogalidou; Wikrom W Karnsakul; Bettina Hansen; Henkjan J Verkade Journal: Hepatology Date: 2021-07-13 Impact factor: 17.425