| Author |
Jiang, XX; Liu, K; Jiang, HZ; Yin, HR; Wang, ED; Cheng, H; Yuan, FX; Xiao, F; Wang, FF; Lu, W; Peng, B; Shu, YS; Li, XY; Chen, SH; Guo, FF |
| Abstract |
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 accumula-tion of lysosomal g-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 resis-tance 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. |
