CiR-EIS alleviates metabolic dysfunction-associated steatohepatitis by modulating macrophage polarization involving the miR-548m/IGF1 axis

IF 6.6 2区医学 Q1 NUTRITION & DIETETICS

Clinical nutrition Pub Date : 2025-05-14 DOI:10.1016/j.clnu.2025.05.009

Xiaoman Chen , Zhiping Wan , Lili Wu , Xiang Cai , Hang Si , Xiaoquan Liu , Qiyi Zhao , Fen Xu , Hong Deng

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引用次数: 0

Abstract

Background & aims

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant public health concern, with macrophage phenotypes implicated in its progression. Although extensive inflammation-suppressing circular RNA (ciR-EIS, formerly named as hsa_circ_0008882) has been implicated in inflammation regulation, its role in macrophage polarization within the context of MASH remains unexplored. This study aimed to clarify the effect of ciR-EIS on macrophage polarization in MASH.

Methods

Immunofluorescence-fluorescence in situ hybridization was used to evaluate the localization of ciR-EIS in human liver sections. THP-1-derived macrophages (TDMs) were utilized to study ciR-EIS functions in vitro. Flow cytometry and RT-qPCR were employed to evaluate macrophage polarization after transfection. Bodipy assay was used to measure lipid buildup in HepG2 cells. Immunohistochemistry was used to confirm liver insulin-like growth factor 1 (IGF1) expression. Retrospective clinical records were analyzed to examine the association between cir-EIS, IGF1, and MASH.

Results

CiR-EIS was downregulated in patients with MASH and colocalized with the macrophage marker CD68. CiR-EIS and mitochondrially encoded NADH dehydrogenase 5 (MT-ND5) were downregulated in M1 macrophages and upregulated in M2 macrophages. TDM-derived supernatants overexpressed ciR-EIS, significantly reducing HepG2 lipid deposition and inhibiting LX2 proliferation. Overexpression of ciR-EIS in TDMs significantly inhibited M1 macrophage markers CD86, interleukin-1 beta, and tumor necrosis factor-alpha while enhancing M2 macrophage markers CD163 and CD206. CiR-EIS regulated macrophage polarization in a manner involving the miR-548m/IGF1 axis. Serum IGF1 levels were positively correlated with ciR-EIS, and both of them were notably reduced in patients with MASH and inversely correlated with APRI and FIB-4 scores.

Conclusions

CiR-EIS regulates macrophage polarization in a manner involving the miR-548/IGF1 axis, thereby reducing hepatocyte lipid accumulation and stellate cell proliferation in MASH. It demonstrates potential as a diagnostic marker and therapeutic target for MASH.

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cirr - eis通过调节涉及miR-548m/IGF1轴的巨噬细胞极化来减轻代谢功能障碍相关的脂肪性肝炎

背景,代谢功能障碍相关脂肪性肝炎（MASH）是一个重要的公共卫生问题，巨噬细胞表型与其进展有关。尽管广泛的炎症抑制环状RNA （cirr - eis，以前被命名为hsa_circ_0008882）与炎症调节有关，但其在MASH背景下巨噬细胞极化中的作用仍未被探索。本研究旨在阐明ir - eis对MASH中巨噬细胞极化的影响。方法采用免疫荧光-荧光原位杂交技术对人肝组织中cire - eis的定位进行鉴定。利用thp -1来源的巨噬细胞（tdm）体外研究ir - eis的功能。流式细胞术和RT-qPCR检测转染后巨噬细胞极化情况。采用Bodipy法测定HepG2细胞的脂质积累。免疫组化法检测肝脏胰岛素样生长因子1 （IGF1）的表达。回顾性分析临床记录，以检查cirr - eis、IGF1和MASH之间的关系。结果scir - eis在MASH患者中下调，并与巨噬细胞标志物CD68共定位。mir - eis和线粒体编码的NADH脱氢酶5 （MT-ND5）在M1巨噬细胞中下调，在M2巨噬细胞中上调。tdm衍生的上清液过表达cirr - eis，显著减少HepG2脂质沉积，抑制LX2增殖。在tdm中过表达cire - eis可显著抑制M1巨噬细胞标志物CD86、白细胞介素-1 β和肿瘤坏死因子α，同时增强M2巨噬细胞标志物CD163和CD206。ir - eis以涉及miR-548m/IGF1轴的方式调节巨噬细胞极化。血清IGF1水平与ir - eis呈正相关，在MASH患者中两者均显著降低，与APRI和FIB-4评分呈负相关。结论scir - eis通过参与miR-548/IGF1轴调控巨噬细胞极化，从而减少MASH中肝细胞脂质积累和星状细胞增殖。它显示了作为MASH的诊断标记和治疗靶点的潜力。

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

Clinical nutrition 医学-营养学

CiteScore

14.10

自引率

6.30%

发文量

356

审稿时长

28 days

期刊介绍： Clinical Nutrition, the official journal of ESPEN, The European Society for Clinical Nutrition and Metabolism, is an international journal providing essential scientific information on nutritional and metabolic care and the relationship between nutrition and disease both in the setting of basic science and clinical practice. Published bi-monthly, each issue combines original articles and reviews providing an invaluable reference for any specialist concerned with these fields.