Original Article
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Dec 14, 2009; 15(46): 5789-5798
Published online Dec 14, 2009. doi: 10.3748/wjg.15.5789
Role of the receptor for advanced glycation end products in hepatic fibrosis
Christina Lohwasser, Daniel Neureiter, Yury Popov, Michael Bauer, Detlef Schuppan
Christina Lohwasser, Yury Popov, Michael Bauer, Detlef Schuppan, Department of Medicine I, University of Erlangen-Nuremberg, Erlangen-Nürnberg, D-91054, Germany
Daniel Neureiter, Institute of Pathology, Paracelsus Private Medicine University, Salzburg, A-5020, Austria
Yury Popov, Detlef Schuppan, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
Author contributions: Lohwasser C, Bauer M, Popov Y and Neureiter D performed the experiments; Schuppan D designed the study; Lohwasser C, Neureiter D and Schuppan D wrote the manuscript.
Supported by Grants from the Interdisciplinary Center for Clinical Research (IZKF, Project B39) and the Johannes and Frieda Marohn Foundation of the University of Erlangen-Nuremberg, Germany
Correspondence to: Detlef Schuppan, MD, PhD, Division of Gastroenterology, Beth Israel-Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Dana 506, Boston, MA 02215, United States. dschuppa@bidmc.harvard.edu
Telephone: +1-617-6672371 Fax: +1-617-6672767
Received: July 25, 2009
Revised: October 1, 2009
Accepted: October 8, 2009
Published online: December 14, 2009

AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis.

METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGE-BSA) and Nε-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro.

RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α. RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1(I) mRNA by AGE-BSA.

CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.

Keywords: Advanced glycation end product, Extracellular matrix, Hepatic stellate cell, Matrix metalloproteinase, Myofibroblast, Receptor for advanced glycation end products, Transforming growth factor β, Tissue inhibitor of metalloproteinase, Tumor necrosis factor α