SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2
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 memb...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124722018885 |
| _version_ | 1828067460883939328 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaoxue Jiang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T23:45:49Z |
| format | Article |
| id | doaj.art-59ed0553eff74c9cbe99874180fda098 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T23:45:49Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-59ed0553eff74c9cbe99874180fda0982023-01-11T04:28:46ZengElsevierCell Reports2211-12472023-01-01421111984SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2Xiaoxue Jiang0Kan Liu1Haizhou Jiang2Hanrui Yin3En-duo Wang4Hong Cheng5Feixiang Yuan6Fei Xiao7Fenfen Wang8Wei Lu9Bo Peng10Yousheng Shu11Xiaoying Li12Shanghai Chen13Feifan Guo14Zhongshan 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, ChinaCAS 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, ChinaCAS 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, ChinaCAS 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, ChinaState 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, ChinaState 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, ChinaZhongshan 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, ChinaZhongshan 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, ChinaCAS 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, ChinaZhongshan 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, ChinaZhongshan 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, ChinaZhongshan 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, ChinaZhongshan 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, ChinaZhongshan 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, ChinaZhongshan 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124722018885CP: Metabolism |
| spellingShingle | 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 SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 Cell Reports CP: Metabolism |
| title | SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 |
| title_full | SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 |
| title_fullStr | SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 |
| title_full_unstemmed | SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 |
| title_short | SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2 |
| title_sort | slc7a14 imports gaba to lysosomes and impairs hepatic insulin sensitivity via inhibiting mtorc2 |
| topic | CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124722018885 |
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