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

• 成果类型: Article
• 署名作者: Ding, Kaixin; Zhang, Zhipeng; Han, Zhengbin; Shi, Lei; Li, Xinzhi; Liu, Yutong; Li, Zhenzhi; Zhao, Chongchong; Cui, Yifeng; Zhou, Liying; Xu, Bolin; Zhou, Wenjing; Zhao, Yikui; Wang, Zhiqiang; Huang, He; Xie, Liwei; Chen, Xiao-wei; Chen, Zheng
• 署名单位: Harbin Institute of Technology; Jilin University; Harbin Medical University; Fudan University; Peking University; Peking University; Guangdong Academy of Sciences
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13975
• DOI: 10.1126/science.adp4120
• 发表日期: 2025-02-28
• 关键词: rna demethylase; metabolism; binding; lipogenesis; fibrosis; GROWTH

摘要

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.