SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2
| Autor: | 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, Feifan Guo |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Cell Reports, Vol 42, Iss 1, Pp 111984- (2023) |
| Druh dokumentu: | article |
| ISSN: | 2211-1247 99874180 |
| DOI: | 10.1016/j.celrep.2022.111984 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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