{"title":"BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH.","authors":"Yi Chen, Kangjie Xie, Caiyang Chen, Xihui Wang, Chenchen Ma, Zhangxiang Huang, Yingfu Jiao, Weifeng Yu","doi":"10.1186/s10020-025-01275-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>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.</p><p><strong>Methods & results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"213"},"PeriodicalIF":6.4000,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123767/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10020-025-01275-6","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.