4EBP2-regulated protein translation has a critical role in high-fat diet-induced insulin resistance in hepatocytes
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:299 |
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| Enthalten in: |
The Journal of biological chemistry - 299(2023), 11 vom: 20. Nov., Seite 105315 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Han, Xiao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.11.2023 Date Revised 06.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105315 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 4EBP2 | |
| 650 | 4 | |a hepatocyte | |
| 650 | 4 | |a insulin resistance | |
| 650 | 4 | |a palmitic acid | |
| 650 | 4 | |a proteomics | |
| 650 | 7 | |a Carrier Proteins |2 NLM | |
| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a Palmitic Acid |2 NLM | |
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| 650 | 7 | |a Eif4ebp2 protein, mouse |2 NLM | |
| 700 | 1 | |a Yang, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Zhanwu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Tian |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Weiqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Guanfei |e verfasserin |4 aut | |
| 700 | 1 | |a Pi, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Jiangang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Huadong |e verfasserin |4 aut | |
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