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The function of the Receptor for Advanced Glycation End Products (RAGE) in ductular reaction-mediated liver fibrosis during cholestasis

ABSTRACT: 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 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, mass spectrometry and in vitro analyses, we investigated the role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Employing mass spectrometry analyses of soluble factors of in vitro cultured wildtype and RAGE deficient BECs Notch ligand Jagged1 was found to be secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Peter Angel

LAB HEAD: Peter Angel

PROVIDER: PXD065854 | Pride | 2025-07-16

REPOSITORIES: pride

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			Action	DRS
	Gel.png	Other
	ML0487-3_new.fasta	Fasta
	UP000000589_10090.fasta	Fasta
	UP000009136_9913.fasta	Fasta
	mqpar.xml	Xml

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Project description: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 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 remains elusive. In this study, we aimed to 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 revealed the central role of 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.

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