First Author | Jiang X | Year | 2023 |
Journal | Cell Rep | Volume | 42 |
Issue | 1 | Pages | 111984 |
PubMed ID | 36640347 | Mgi Jnum | J:333445 |
Mgi Id | MGI:7434070 | Doi | 10.1016/j.celrep.2022.111984 |
Citation | Jiang X, et al. (2023) SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2. Cell Rep 42(1):111984 |
abstractText | 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 gamma-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. |