Lipocalin 13 Mitigates Metabolic Dysfunction-Associated Steatotic Liver Disease Through Inhibiting the ADRB2/ERK Signalling Pathway

IF 6.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2026-09-07 DOI:10.1111/liv.70858

Xingliang Qin, Yu Hong, Weishu Ren, Gewen Lei, Weiwei Zhou, Siqi Wu, Zifan Lin, Yongyao Tan, Kaiyuan Cao, Zhen Wei, Hong Shi, Xun Zhu, Guohong Wei

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Abstract

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by abnormalities in secreted protein biosynthesis. A comprehensive understanding of secreted proteins could lead to improved diagnostics and therapies for MASLD. This study investigates the therapeutic potential of lipocalin 13 (LCN13), a lipocain family protein, in MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH).

Methods

We screened critical lipocalins linked to MASLD using the Gene Expression Omnibus databases, analysing data from both mice and humans. The functional role of LCN13 was assessed in global knockout mice and in two murine MASLD models. We investigated LCN13's impact on glucose intolerance, insulin resistance, hepatic steatosis, and metabolic dysfunction in C57BL/6J mice subjected to high-fat and methionine–choline-deficient diets. The methodologies employed included Western blotting, quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), haematoxylin and eosin staining (H&E), and Oil Red O staining. Furthermore, we employed co-immunoprecipitation (co-IP), LC–MS/MS, Western blotting, and qPCR to investigate the underlying mechanisms involved.

Results

LCN13 expression was significantly reduced in both mouse and human MASLD cases. Administration of recombinant LCN13 protein (rLCN13) improved conditions like hepatic steatosis, inflammation, and hepatocyte injury in diet-challenged mice, whereas LCN13 knockout worsened these effects. Mechanistically, LCN13 was found to inhibit the activation of the ERK signalling pathway by interacting with the extracellular loop 2 (ECL2) of the ADRB2, thereby representing a novel target for LCN13. This interaction suppressed CD36 expression, impacting lipid transport signalling and subsequently slowing the MASLD and MASH progression.

Conclusions

Our findings highlight the protective role of LCN13 in MASLD and MASH, offering a new therapeutic approach for these metabolic disorders.

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脂钙蛋白13通过抑制ADRB2/ERK信号通路减轻代谢功能障碍相关的脂肪变性肝病

背景：代谢功能障碍相关脂肪变性肝病（MASLD）以分泌蛋白生物合成异常为特征。对分泌蛋白的全面了解可以改善MASLD的诊断和治疗。本研究探讨了脂载蛋白家族蛋白脂载蛋白13 （LCN13）在MASLD及其更严重的形式——代谢功能障碍相关脂肪性肝炎（MASH）中的治疗潜力。方法：我们使用基因表达综合数据库筛选与MASLD相关的关键脂质体，分析来自小鼠和人类的数据。在全基因敲除小鼠和两种小鼠MASLD模型中评估了LCN13的功能作用。我们研究了LCN13对高脂肪和蛋氨酸-胆碱缺乏饮食的C57BL/6J小鼠葡萄糖耐受不良、胰岛素抵抗、肝脏脂肪变性和代谢功能障碍的影响。采用的方法包括Western blotting、定量实时聚合酶链反应（qPCR）、酶联免疫吸附试验（ELISA）、血红素和伊红染色（H&E）和油红O染色。此外，我们采用共免疫沉淀（co-IP）， LC-MS/MS， Western blotting和qPCR来研究相关的潜在机制。结果：LCN13在小鼠和人MASLD中表达均显著降低。重组LCN13蛋白（rLCN13）改善了饮食挑战小鼠的肝脂肪变性、炎症和肝细胞损伤等疾病，而LCN13敲除使这些作用恶化。从机制上讲，LCN13通过与ADRB2的细胞外环2 （ECL2）相互作用抑制ERK信号通路的激活，从而代表了LCN13的新靶点。这种相互作用抑制CD36的表达，影响脂质转运信号，随后减缓MASLD和MASH的进展。结论：我们的研究结果突出了LCN13在MASLD和MASH中的保护作用，为这些代谢紊乱提供了新的治疗方法。

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

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.