Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice
© 2022. The Author(s)..
Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 23. Feb., Seite 1025 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Huanqing [VerfasserIn] |
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| Links: |
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| Themen: |
Cytoskeletal Proteins |
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| Anmerkungen: |
Date Completed 12.04.2022 Date Revised 24.10.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-28692-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM337291004 |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation | ||
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| 700 | 1 | |a Zhou, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Yiming |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Sixiong |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Xiaoting |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiaoqian |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Xuenong |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Huiling |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Guozhi |e verfasserin |4 aut | |
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