Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, 131 Dong'an Road, Shanghai 200032, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Rep. 2023 Jan 31;42(1):111984. doi: 10.1016/j.celrep.2022.111984. Epub 2023 Jan 10.
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.
溶酶体氨基酸积累与多种疾病有关，但它在胰岛素抵抗（2 型糖尿病和许多代谢性疾病的核心机制）中的作用尚不清楚。在这项研究中，我们发现胰岛素抵抗小鼠肝脏中溶酶体膜蛋白溶质载体家族 7 成员 14（SLC7A14）的表达增加。通过失活和功能获得实验证明了 SLC7A14 对胰岛素抵抗的促进作用。进一步证明 SLC7A14 是一种转运蛋白，导致溶酶体 γ-氨基丁酸（GABA）的积累，通过抑制 mTOR 复合物 2（mTORC2）的活性诱导胰岛素抵抗。这些结果确立了溶酶体氨基酸与胰岛素抵抗之间的因果关系，并表明 SLC7A14 抑制可能为治疗与胰岛素抵抗相关和 GABA 相关的疾病提供一种治疗策略，并可能为 mTORC2 的上游机制提供深入了解，mTORC2 是许多重要过程的主调控因子。
