SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2

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

doi:10.1016/j.celrep.2022.111984

SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2

Cell Rep. 2023 Jan 31;42(1):111984. doi: 10.1016/j.celrep.2022.111984. Epub 2023 Jan 10.

Authors

Xiaoxue Jiang¹, Kan Liu², Haizhou Jiang², Hanrui Yin², En-Duo Wang³, Hong Cheng³, Feixiang Yuan¹, Fei Xiao¹, Fenfen Wang², Wei Lu¹, Bo Peng¹, Yousheng Shu¹, Xiaoying Li¹, Shanghai Chen¹, Feifan Guo⁴

Affiliations

¹ 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.
² 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.
³ State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁴ 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. Electronic address: ffguo@fudan.edu.cn.

PMID: 36640347
DOI: 10.1016/j.celrep.2022.111984

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 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.

Keywords: CP: Metabolism; GABA; SLC7A14; amino acid; insulin resistance; liver; lysosome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / metabolism
Animals
Diabetes Mellitus, Type 2* / metabolism
Insulin Resistance*
Lysosomes / metabolism
Mechanistic Target of Rapamycin Complex 2 / metabolism
Mice
gamma-Aminobutyric Acid / metabolism

Substances

Mechanistic Target of Rapamycin Complex 2
Amino Acids
gamma-Aminobutyric Acid