Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling.

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-02-28 DOI:10.1126/science.adp4120

Kaixin Ding, Zhipeng Zhang, Zhengbin Han, Lei Shi, Xinzhi Li, Yutong Liu, Zhenzhi Li, Chongchong Zhao, Yifeng Cui, Liying Zhou, Bolin Xu, Wenjing Zhou, Yikui Zhao, Zhiqiang Wang, He Huang, Liwei Xie, Xiao-Wei Chen, Zheng Chen

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引用次数: 0

Abstract

Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N⁶-methyladenosine (m⁶A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.

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肝脏ALKBH5通过GCGR和mTORC1信号独立调节葡萄糖和脂质稳态。

维持葡萄糖和脂质稳态对健康至关重要，因为调节失调会导致代谢性疾病，如2型糖尿病（T2DM）和代谢功能障碍相关的脂肪性肝病（MAFLD）。本研究发现烷基化修复同源蛋白5 （ALKBH5）是一种RNA n6 -甲基腺苷（m6A）去甲基化酶，是代谢性疾病的主要调节因子。肥胖期间，ALKBH5在肝脏中上调，并被蛋白激酶A磷酸化，导致其易位到细胞质中。肝细胞特异性缺失Alkbh5通过抑制胰高血糖素受体（GCGR）和哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）信号通路来降低葡萄糖和脂质。靶向敲低肝脏Alkbh5可逆转糖尿病小鼠的T2DM和MAFLD，突出其治疗潜力。本研究揭示了ALKBH5通过整合GCGR和mTORC1途径协调葡萄糖和脂质稳态的调控机制，为代谢性疾病的调控提供了新的思路。

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

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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