BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH
Abstract Background and aims Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic st...
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BMC
2025-05-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01275-6 |
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| author | Yi Chen Kangjie Xie Caiyang Chen Xihui Wang Chenchen Ma Zhangxiang Huang Yingfu Jiao Weifeng Yu |
| author_facet | Yi Chen Kangjie Xie Caiyang Chen Xihui Wang Chenchen Ma Zhangxiang Huang Yingfu Jiao Weifeng Yu |
| author_sort | Yi Chen |
| collection | DOAJ |
| description | Abstract Background and aims Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic steatosis to MASH. Macrophages, especially anti-inflammatory macrophages, serve as natural immune cells that maintain homeostasis in the immune microenvironment. Here, we aimed to reveal the role of anti-inflammatory macrophages in MASH and investigate the underlying mechanism involved. Methods & results Extracellular vesicles (EVs) were isolated from the supernatant of anti-inflammatory bone marrow-derived macrophages (BMDMs) by ultracentrifugation, and their protein profile was characterized by liquid chromatography–tandem mass spectrometry (LC‒MS/MS) analysis. Murine hepatocytes were stimulated with palmitic acid (PA) followed by treatment with EVs or oxysterol-binding protein-related protein 8 (ORP8/Osbpl8) shRNA. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 3 weeks to establish MASH. The mice were then treated with EVs or shRNA-encoding AAV. In vitro and ex vivo experiments revealed that extracellular vesicles derived from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity during MASH. We identified Osbpl8 as a vital component of M2-BMDMs by LC–MS/MS analysis and found that Osbpl8 remodels lipid metabolism by inhibiting excessive IRE1α-XBP1-related ER stress. Furthermore, Osbpl8-enriched M2-BMDM-EVs promoted anti-inflammatory and antilipotoxic effects and could be a novel therapeutic target for the clinical treatment of MASH. Conclusions Our findings indicate that Osbpl8 derived from EVs secreted by anti-inflammatory BMDMs plays important roles in intercellular communication between macrophages and hepatocytes, revealing a novel regulatory mechanism of macrophage homoeostasis in MASH. |
| format | Article |
| id | doaj-art-8ea6b1828698440d94c9fcf2b024e99f |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-8ea6b1828698440d94c9fcf2b024e99f2025-08-20T03:43:16ZengBMCMolecular Medicine1528-36582025-05-0131111510.1186/s10020-025-01275-6BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASHYi Chen0Kangjie Xie1Caiyang Chen2Xihui Wang3Chenchen Ma4Zhangxiang Huang5Yingfu Jiao6Weifeng Yu7Department of Anesthesiology, Renji Hospital, Jiaotong University School of MedicineDepartment of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of MedicineDepartment of Anesthesiology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of SciencesDepartment of Anesthesiology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of SciencesDepartment of Pain Management, The First Affiliated Hospital of Kunming Medical UniversityDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of MedicineDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of MedicineAbstract Background and aims Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic steatosis to MASH. Macrophages, especially anti-inflammatory macrophages, serve as natural immune cells that maintain homeostasis in the immune microenvironment. Here, we aimed to reveal the role of anti-inflammatory macrophages in MASH and investigate the underlying mechanism involved. Methods & results Extracellular vesicles (EVs) were isolated from the supernatant of anti-inflammatory bone marrow-derived macrophages (BMDMs) by ultracentrifugation, and their protein profile was characterized by liquid chromatography–tandem mass spectrometry (LC‒MS/MS) analysis. Murine hepatocytes were stimulated with palmitic acid (PA) followed by treatment with EVs or oxysterol-binding protein-related protein 8 (ORP8/Osbpl8) shRNA. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 3 weeks to establish MASH. The mice were then treated with EVs or shRNA-encoding AAV. In vitro and ex vivo experiments revealed that extracellular vesicles derived from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity during MASH. We identified Osbpl8 as a vital component of M2-BMDMs by LC–MS/MS analysis and found that Osbpl8 remodels lipid metabolism by inhibiting excessive IRE1α-XBP1-related ER stress. Furthermore, Osbpl8-enriched M2-BMDM-EVs promoted anti-inflammatory and antilipotoxic effects and could be a novel therapeutic target for the clinical treatment of MASH. Conclusions Our findings indicate that Osbpl8 derived from EVs secreted by anti-inflammatory BMDMs plays important roles in intercellular communication between macrophages and hepatocytes, revealing a novel regulatory mechanism of macrophage homoeostasis in MASH.https://doi.org/10.1186/s10020-025-01275-6Bone marrow-derived macrophagesEndoplasmic reticulum stressExtracellular vesiclesLipotoxicityMetabolic dysfunction-associated steatohepatitis |
| spellingShingle | Yi Chen Kangjie Xie Caiyang Chen Xihui Wang Chenchen Ma Zhangxiang Huang Yingfu Jiao Weifeng Yu BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH Molecular Medicine Bone marrow-derived macrophages Endoplasmic reticulum stress Extracellular vesicles Lipotoxicity Metabolic dysfunction-associated steatohepatitis |
| title | BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH |
| title_full | BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH |
| title_fullStr | BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH |
| title_full_unstemmed | BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH |
| title_short | BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH |
| title_sort | bmdm derived orp8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with mash |
| topic | Bone marrow-derived macrophages Endoplasmic reticulum stress Extracellular vesicles Lipotoxicity Metabolic dysfunction-associated steatohepatitis |
| url | https://doi.org/10.1186/s10020-025-01275-6 |
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