Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-02-25 Epub Date: 2025-01-30 DOI:10.1016/j.celrep.2025.115251

Min Chen, Yang Li, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Lin-Jing Yan, Shan Li, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo

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引用次数: 0

Abstract

Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.

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运动诱导的脂肪因子Nrg4通过破坏肝脏cGAS-STING信号通路来缓解MASLD。

运动是改善代谢功能障碍相关脂肪变性肝病（MASLD）的一种有效的非药物策略。神经调节蛋白-4 （Nrg4）是一种脂肪因子，在代谢稳态中具有潜在作用。先前的研究结果表明Nrg4在运动中上调，Nrg4可减少肝脏脂肪变性，但其潜在机制尚不完全清楚。在这里，我们发现脂肪Nrg4在小鼠运动后被Pparγ反激活。腺相关病毒（AAV）介导的脂肪Nrg4的敲除以及肝细胞特异性敲除Erbb4 （Nrg4受体）损害了小鼠运动介导的MASLD缓解。相反，aav介导的脂肪Nrg4过表达与运动协同可减轻小鼠的MASLD。机制上，Nrg4/Erbb4/AKT信号通路促进环鸟苷单磷酸腺苷合成酶（cGAS）磷酸化，减弱其酶活性，从而抑制cGAS- sting途径介导的肝细胞炎症和脂肪变性。因此，Nrg4作为一种运动诱导的脂肪因子，参与脂肪-肝组织通信以对抗MASLD。

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

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.