Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis
Abstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-023-00721-7 |
| _version_ | 1797558924543524864 |
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| author | Tingli Guo Wenhui Yan Xin Cui Na Liu Xiaotong Wei Yuzhuo Sun KeXin Fan Jieyun Liu Yuanyuan Zhu Zhuanzhuan Wang Yilei Zhang Lina Chen |
| author_facet | Tingli Guo Wenhui Yan Xin Cui Na Liu Xiaotong Wei Yuzhuo Sun KeXin Fan Jieyun Liu Yuanyuan Zhu Zhuanzhuan Wang Yilei Zhang Lina Chen |
| author_sort | Tingli Guo |
| collection | DOAJ |
| description | Abstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD. Methods Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture. Results Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo. Conclusions These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis. |
| first_indexed | 2024-03-10T17:38:20Z |
| format | Article |
| id | doaj.art-2535d181d9854339ac5dfd3b41529ddd |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-03-10T17:38:20Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-2535d181d9854339ac5dfd3b41529ddd2023-11-20T09:46:19ZengBMCMolecular Medicine1528-36582023-09-0129111710.1186/s10020-023-00721-7Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosisTingli Guo0Wenhui Yan1Xin Cui2Na Liu3Xiaotong Wei4Yuzhuo Sun5KeXin Fan6Jieyun Liu7Yuanyuan Zhu8Zhuanzhuan Wang9Yilei Zhang10Lina Chen11Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterKey Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of EducationDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi’an Jiaotong University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterAbstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD. Methods Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture. Results Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo. Conclusions These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis.https://doi.org/10.1186/s10020-023-00721-7LiraglutideType 2 diabetes mellitusNon-alcoholic fatty liver diseaseLipid peroxidationFerroptosis |
| spellingShingle | Tingli Guo Wenhui Yan Xin Cui Na Liu Xiaotong Wei Yuzhuo Sun KeXin Fan Jieyun Liu Yuanyuan Zhu Zhuanzhuan Wang Yilei Zhang Lina Chen Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis Molecular Medicine Liraglutide Type 2 diabetes mellitus Non-alcoholic fatty liver disease Lipid peroxidation Ferroptosis |
| title | Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis |
| title_full | Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis |
| title_fullStr | Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis |
| title_full_unstemmed | Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis |
| title_short | Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis |
| title_sort | liraglutide attenuates type 2 diabetes mellitus associated non alcoholic fatty liver disease by activating ampk acc signaling and inhibiting ferroptosis |
| topic | Liraglutide Type 2 diabetes mellitus Non-alcoholic fatty liver disease Lipid peroxidation Ferroptosis |
| url | https://doi.org/10.1186/s10020-023-00721-7 |
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