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Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance
The E3 ubiquitin ligase FBW7 plays critical roles in multiple pathological and physiological processes. Here, we report that after high-fat diet (HFD) feeding for 16 weeks, myeloid-specific FBW7-deficient mice demonstrate increased redox stress, inflammatory responses and insulin resistance. Macroph...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451763/ https://www.ncbi.nlm.nih.gov/pubmed/32853822 http://dx.doi.org/10.1016/j.redox.2020.101688 |
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author | Wang, Cheng Chao, Yuelin Xu, Wenjing Liu, Zhaoyu Wang, Huan Huang, Kai |
author_facet | Wang, Cheng Chao, Yuelin Xu, Wenjing Liu, Zhaoyu Wang, Huan Huang, Kai |
author_sort | Wang, Cheng |
collection | PubMed |
description | The E3 ubiquitin ligase FBW7 plays critical roles in multiple pathological and physiological processes. Here, we report that after high-fat diet (HFD) feeding for 16 weeks, myeloid-specific FBW7-deficient mice demonstrate increased redox stress, inflammatory responses and insulin resistance. Macrophages activation under FBW7 deficiency decreases substrate flux through the pentose phosphate pathway (PPP) to produce less equivalents (NADPH and GSH) and aggravate the generation of intracellular reactive oxygen species (ROS) in macrophages, thereby over-activating proinflammatory reaction. Mechanistically, we identify that pyruvate kinase muscle isozyme M2 (PKM2) is a new bona fide ubiquitin substrate of SCF(FBW7). While challenged with HFD stress, pharmacological inhibition of PKM2 protects FBW7-deficient macrophages against production of ROS, proinflammatory reaction and insulin resistance. Intriguingly, we further find an inverse correlation between FBW7 level and relative higher H(2)O(2) level and the severity of obesity-related diabetes. Overall, the results suggest that FBW7 can play a crucial role in modulating inflammatory response through maintaining the intracellular redox homeostasis during HFD insults. |
format | Online Article Text |
id | pubmed-7451763 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-74517632020-08-31 Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance Wang, Cheng Chao, Yuelin Xu, Wenjing Liu, Zhaoyu Wang, Huan Huang, Kai Redox Biol Research Paper The E3 ubiquitin ligase FBW7 plays critical roles in multiple pathological and physiological processes. Here, we report that after high-fat diet (HFD) feeding for 16 weeks, myeloid-specific FBW7-deficient mice demonstrate increased redox stress, inflammatory responses and insulin resistance. Macrophages activation under FBW7 deficiency decreases substrate flux through the pentose phosphate pathway (PPP) to produce less equivalents (NADPH and GSH) and aggravate the generation of intracellular reactive oxygen species (ROS) in macrophages, thereby over-activating proinflammatory reaction. Mechanistically, we identify that pyruvate kinase muscle isozyme M2 (PKM2) is a new bona fide ubiquitin substrate of SCF(FBW7). While challenged with HFD stress, pharmacological inhibition of PKM2 protects FBW7-deficient macrophages against production of ROS, proinflammatory reaction and insulin resistance. Intriguingly, we further find an inverse correlation between FBW7 level and relative higher H(2)O(2) level and the severity of obesity-related diabetes. Overall, the results suggest that FBW7 can play a crucial role in modulating inflammatory response through maintaining the intracellular redox homeostasis during HFD insults. Elsevier 2020-08-15 /pmc/articles/PMC7451763/ /pubmed/32853822 http://dx.doi.org/10.1016/j.redox.2020.101688 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Wang, Cheng Chao, Yuelin Xu, Wenjing Liu, Zhaoyu Wang, Huan Huang, Kai Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title | Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title_full | Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title_fullStr | Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title_full_unstemmed | Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title_short | Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
title_sort | myeloid fbw7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451763/ https://www.ncbi.nlm.nih.gov/pubmed/32853822 http://dx.doi.org/10.1016/j.redox.2020.101688 |
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