TY  - JOUR
AU  - Lam, Wai-Ling Macrina
AU  - Gabernet, Gisela
AU  - Poth, Tanja
AU  - Sator-Schmitt, Melanie
AU  - Oquendo, Morgana Barroso
AU  - Walter, Bettina
AU  - Lohr, Sabrina
AU  - De Ponti, Aurora
AU  - Weiß, Lena
AU  - Schneider, Martin
AU  - Helm, Dominic
AU  - Müller-Decker, Karin
AU  - Schirmacher, Peter
AU  - Heikenwälder, Mathias
AU  - Klingmüller, Ursula
AU  - Schneller, Doris
AU  - Geisler, Fabian
AU  - Nahnsen, Sven
AU  - Angel, Peter
TI  - RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis.
JO  - EMBO reports
VL  - 26
IS  - 3
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DKFZ-2025-00044
SP  - 880-907
PY  - 2025
N1  - DKFZ-ZMBH Alliance / 2025 Feb;26(3):880-907 / #EA:A100#LA:A100#
AB  - Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
KW  - Biliary Epithelial Cells (Other)
KW  - Chronic Liver Injury (Other)
KW  - Genetically Modified Mice (Other)
KW  - Hepatic Stellate Cells (Other)
KW  - Receptor for Advanced Glycation End Products (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39747668
DO  - DOI:10.1038/s44319-024-00356-7
UR  - https://inrepo02.dkfz.de/record/296114
ER  -