Article
作者: Li, Xinzhi ; Chen, Zheng ; Zhou, Liying ; Ding, Kaixin ; Zhang, Zhipeng ; Wang, Zhiqiang ; Xu, Bolin ; Huang, He ; Zhou, Wenjing ; Chen, Xiao-wei ; Li, Zhenzhi ; Zhao, Yikui ; Cui, Yifeng ; Han, Zhengbin ; Liu, Yutong ; Zhao, Chongchong ; Shi, Lei ; Xie, Liwei
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 N
6
-methyladenosine (m
6
A) 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.