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