1. SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2
- Author
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Xiaoxue Jiang, Kan Liu, Haizhou Jiang, Hanrui Yin, En-duo Wang, Hong Cheng, Feixiang Yuan, Fei Xiao, Fenfen Wang, Wei Lu, Bo Peng, Yousheng Shu, Xiaoying Li, Shanghai Chen, and Feifan Guo
- Subjects
CP: Metabolism ,Biology (General) ,QH301-705.5 - Abstract
Summary: Lysosomal amino acid accumulation is implicated in several diseases, but its role in insulin resistance, the central mechanism to type 2 diabetes and many metabolic diseases, is unclear. In this study, we show the hepatic expression of lysosomal membrane protein solute carrier family 7 member 14 (SLC7A14) is increased in insulin-resistant mice. The promoting effect of SLC7A14 on insulin resistance is demonstrated by loss- and gain-of-function experiments. SLC7A14 is further demonstrated as a transporter resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)’s activity. These results establish a causal link between lysosomal amino acids and insulin resistance and suggest that SLC7A14 inhibition may provide a therapeutic strategy in treating insulin resistance-related and GABA-related diseases and may provide insights into the upstream mechanisms for mTORC2, the master regulator in many important processes.
- Published
- 2023
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