FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease
Abstract Background Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying t...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-019-0099-9 |
| _version_ | 1818188487196672000 |
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| author | Cheng Zhang Feng Chen Li Feng Qun Shan Gui-Hong Zheng Yong-Jian Wang Jun Lu Shao-Hua Fan Chun-Hui Sun Dong-Mei Wu Meng-Qiu Li Bin Hu Qing-Qing Wang Zi-Feng Zhang Yuan-Lin Zheng |
| author_facet | Cheng Zhang Feng Chen Li Feng Qun Shan Gui-Hong Zheng Yong-Jian Wang Jun Lu Shao-Hua Fan Chun-Hui Sun Dong-Mei Wu Meng-Qiu Li Bin Hu Qing-Qing Wang Zi-Feng Zhang Yuan-Lin Zheng |
| author_sort | Cheng Zhang |
| collection | DOAJ |
| description | Abstract Background Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying the underlying mechanisms may provide therapeutic targets for NAFLD. Recently, F-box- and WD repeat domain-containing 7 (FBXW7) exhibits a regulatory role in hepatic glucose and lipid metabolism. This study aims to investigate whether FBXW7 controls high-mobility group box 1 protein (HMGB1)-mediated innate immune signaling to improve NAFLD and the mechanism underlying this action. Methods Mice were fed a high-fat diet (HFD) for 12 or 20 weeks to establish NAFLD model. Hepatic overexpression or knockdown of FBXW7 was induced by tail-vein injection of recombinant adenovirus. Some Ad-FBXW7-injected mice fed a HFD were injected intraperitoneally with recombinant mouse HMGB1 to confirm the protective role of FBXW7 in NAFLD via inhibition of HMGB1. Results FBXW7 improves NAFLD and related metabolic parameters without remarkable influence of body weight and food intake. Moreover, FBXW7 markedly ameliorated hepatic inflammation and insulin resistance in the HFD-fed mice. Furthermore, FBXW7 dramatically attenuated the expression and release of HMGB1 in the livers of HFD-fed mice, which is associated with inhibition of protein kinase R (PKR) signaling. Thereby, FBXW7 restrains Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) signaling in HFD-fed mouse livers. In addition, exogenous HMGB1 treatment abolished FBXW7-mediated inhibition of hepatic inflammation and insulin resistance in HFD-fed mouse livers. Conclusions Our results demonstrate a protective role of FBXW7 in NAFLD by abating HMGB1-mediated innate immune signaling to suppress inflammation and consequent insulin resistance, suggesting that FBXW7 is a potential target for therapeutic intervention in NAFLD development. |
| first_indexed | 2024-12-11T23:27:42Z |
| format | Article |
| id | doaj.art-1dad3cc361f14571bbdd3c222629a26c |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-11T23:27:42Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-1dad3cc361f14571bbdd3c222629a26c2022-12-22T00:46:08ZengBMCMolecular Medicine1076-15511528-36582019-06-0125111510.1186/s10020-019-0099-9FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver diseaseCheng Zhang0Feng Chen1Li Feng2Qun Shan3Gui-Hong Zheng4Yong-Jian Wang5Jun Lu6Shao-Hua Fan7Chun-Hui Sun8Dong-Mei Wu9Meng-Qiu Li10Bin Hu11Qing-Qing Wang12Zi-Feng Zhang13Yuan-Lin Zheng14School of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversityKey Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, Jiangsu Normal UniversityKey Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversitySchool of Life Science, Jiangsu Normal UniversityAbstract Background Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying the underlying mechanisms may provide therapeutic targets for NAFLD. Recently, F-box- and WD repeat domain-containing 7 (FBXW7) exhibits a regulatory role in hepatic glucose and lipid metabolism. This study aims to investigate whether FBXW7 controls high-mobility group box 1 protein (HMGB1)-mediated innate immune signaling to improve NAFLD and the mechanism underlying this action. Methods Mice were fed a high-fat diet (HFD) for 12 or 20 weeks to establish NAFLD model. Hepatic overexpression or knockdown of FBXW7 was induced by tail-vein injection of recombinant adenovirus. Some Ad-FBXW7-injected mice fed a HFD were injected intraperitoneally with recombinant mouse HMGB1 to confirm the protective role of FBXW7 in NAFLD via inhibition of HMGB1. Results FBXW7 improves NAFLD and related metabolic parameters without remarkable influence of body weight and food intake. Moreover, FBXW7 markedly ameliorated hepatic inflammation and insulin resistance in the HFD-fed mice. Furthermore, FBXW7 dramatically attenuated the expression and release of HMGB1 in the livers of HFD-fed mice, which is associated with inhibition of protein kinase R (PKR) signaling. Thereby, FBXW7 restrains Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) signaling in HFD-fed mouse livers. In addition, exogenous HMGB1 treatment abolished FBXW7-mediated inhibition of hepatic inflammation and insulin resistance in HFD-fed mouse livers. Conclusions Our results demonstrate a protective role of FBXW7 in NAFLD by abating HMGB1-mediated innate immune signaling to suppress inflammation and consequent insulin resistance, suggesting that FBXW7 is a potential target for therapeutic intervention in NAFLD development.http://link.springer.com/article/10.1186/s10020-019-0099-9FBXW7HMGB1Innate immunityMetaflammationInsulin resistanceNAFLD |
| spellingShingle | Cheng Zhang Feng Chen Li Feng Qun Shan Gui-Hong Zheng Yong-Jian Wang Jun Lu Shao-Hua Fan Chun-Hui Sun Dong-Mei Wu Meng-Qiu Li Bin Hu Qing-Qing Wang Zi-Feng Zhang Yuan-Lin Zheng FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease Molecular Medicine FBXW7 HMGB1 Innate immunity Metaflammation Insulin resistance NAFLD |
| title | FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| title_full | FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| title_fullStr | FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| title_full_unstemmed | FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| title_short | FBXW7 suppresses HMGB1-mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| title_sort | fbxw7 suppresses hmgb1 mediated innate immune signaling to attenuate hepatic inflammation and insulin resistance in a mouse model of nonalcoholic fatty liver disease |
| topic | FBXW7 HMGB1 Innate immunity Metaflammation Insulin resistance NAFLD |
| url | http://link.springer.com/article/10.1186/s10020-019-0099-9 |
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