Hepatocyte specific Rab27a knockout aggravates metabolic dysfunction associated fatty liver disease.

Abstract

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.