RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-01-02 DOI:10.1038/s44319-024-00356-7

Wai-Ling Macrina Lam, Gisela Gabernet, Tanja Poth, Melanie Sator-Schmitt, Morgana Barroso Oquendo, Bettina Kast, Sabrina Lohr, Aurora de Ponti, Lena Weiß, Martin Schneider, Dominic Helm, Karin Müller-Decker, Peter Schirmacher, Mathias Heikenwälder, Ursula Klingmüller, Doris Schneller, Fabian Geisler, Sven Nahnsen, Peter Angel

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引用次数: 0

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 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.

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RAGE是胆汁淤积期间导管反应介导纤维化的关键调节因子。

胆管反应（DR）是胆汁淤积性疾病的标志，表现为胆道上皮细胞（BECs）内衬的胆管增生。它通常与纤维化和肝功能衰竭的风险增加有关。晚期糖基化终产物受体（RAGE）被认为是慢性损伤中DR的关键介质。然而，rage介导的DR与纤维化之间的直接联系以及BECs与肝星状细胞（hsc）之间驱动纤维化的相互作用模式仍然难以捉摸。在这里，我们描述了RAGE在DR期间对BECs的特定功能及其在胆汁淤积背景下与纤维化的潜在关联。采用胆道谱系追踪胆汁淤积性肝损伤小鼠模型，结合全转录组测序和体外分析，我们揭示了bc特异性Rage活性在促进纤维化环境中的作用。RAGE主要在BECs中表达，并对dr起作用。Notch配体Jagged1以RAGE依赖的方式从活化的BECs中分泌，并在反式中向hsc发出信号，最终在胆汁淤积期间增强纤维化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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