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Updated: Mar 20, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Hepatocyte specific Rab27a knockout aggravates metabolic dysfunction associated fatty liver disease
Jia-Ying Hu1, Xin-Yi Liao1, Rong-Zheng Ran2
1Department of Hepatobiliary Surgery Center, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Liver and non-liver Comorbidity Research Center, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
Background:
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a leading cause of chronic liver morbidity, yet its molecular pathogenesis remains incompletely elucidated. Exosomes, a distinct class of extracellular vesicles, facilitate intercellular communication and organ crosstalk. Rab27a is a well-known exosome regulator. This study investigate the role of hepatocyte-specific Rab27a and its regulated hepatocyte-derived exosomes in MAFLD progression.
Methods:
Rab27a expression was quantified via Western blot. Hepatocyte-specific Rab27a knockout (Rab27a-HC-KO) mice were generated using the Cre-loxP system. The severity of hepatic steatosis was assessed using hematoxylin-eosin (H&E) and Oil Red O staining, supplemented by quantitative analysis of hepatic triglyceride (TG) levels. Liver injury was evaluated through serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assays. Serum exosome concentrations were precisely determined using nano-flow cytometry.
Results:
High-fat diet (HFD) feeding triggered the upregulation of the IRF-1-Rab27a signaling axis in the liver, correlating with elevated serum exosome concentrations compared to low-fat diet (LFD) controls. In Rab27a-HC-KO mice, the loss of hepatocyte Rab27a was confirmed via PCR and protein analysis. Notably, Rab27a-HC-KO mice exhibited markedly exacerbated hepatic lipid accumulation, intensified liver injury, and impaired glucose tolerance under metabolic stress. Furthermore, HFD-fed Rab27a-HC-KO mice showed a significant reduction in total serum exosome secretion and depletion of exosomal HMGB1 content.
Conclusion:
Our findings demonstrate that the loss of hepatocyte-specific Rab27a-mediated exosome secretion aggravates MAFLD and associated hepatic damage. These data suggest that hepatocyte-derived exosomes and their HMGB1 cargo may play a protective role by facilitating intrinsic repair pathways, representing a potential therapeutic target for MAFLD.
Insights
Loss of hepatocyte Rab27a impairs exosome secretion, worsening metabolic dysfunction-associated fatty liver disease (MAFLD). Hepatocyte-derived exosomes, particularly HMGB1, may offer protection against liver damage and metabolic stress.
Area of Science:
- Hepatology
- Molecular Biology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant cause of chronic liver disease with unclear molecular mechanisms.
- Exosomes are key mediators of intercellular communication, and Rab27a is a known regulator of exosome release.
- This study investigates the role of hepatocyte-specific Rab27a and its exosomes in MAFLD.
Purpose of the Study:
- To elucidate the role of hepatocyte-specific Rab27a in MAFLD pathogenesis.
- To determine the impact of Rab27a-regulated exosomes on liver health and metabolic function.
- To explore potential therapeutic targets for MAFLD based on exosome function.
Main Methods:
- Quantified Rab27a expression using Western blot.
- Generated hepatocyte-specific Rab27a knockout (Rab27a-HC-KO) mice.
- Assessed hepatic steatosis, liver injury (ALT, AST), glucose tolerance, and serum exosome concentration (nano-flow cytometry).
Main Results:
- High-fat diet (HFD) increased IRF-1-Rab27a signaling and serum exosome levels.
- Rab27a-HC-KO mice showed exacerbated hepatic steatosis, liver injury, and impaired glucose tolerance.
- Loss of Rab27a reduced serum exosome secretion and depleted exosomal HMGB1.
Conclusions:
- Hepatocyte-specific Rab27a is crucial for exosome secretion and mitigating MAFLD.
- Reduced exosome secretion and HMGB1 cargo worsen liver damage and metabolic dysfunction.
- Hepatocyte-derived exosomes and HMGB1 represent potential therapeutic targets for MAFLD.
