Adipose Tissue Macrophages in Metabolic Dysfunction-Associated Steatohepatitis Secrete Extracellular Vesicles That Activate Liver Fibrosis in Obese Male Mice.

Summary

In obese male mice with MASH, adipose tissue macrophages secrete small extracellular vesicles enriched in miR-155 and miR-34a that downregulate Pparg, activate hepatic stellate cells, and exacerbate liver fibrosis. Anti-inflammatory macrophage sEVs ameliorate fibrosis, while miRNA-depleted sEVs lose effect and antagomirs to miR-155/miR-34a block activation, establishing causal roles and a mechanistic extrahepatic signal.

Key Findings

• MASH adipose tissue macrophages secrete sEVs enriched in miR-155 and miR-34a that downregulate Pparg and activate hepatic stellate cells.
• Administration of MASH-ATM sEVs exacerbated liver fibrosis in obese mice, whereas anti-inflammatory macrophage sEVs mitigated fibrosis.
• miRNA-depleted (Dicer knockdown) sEVs lost profibrotic activity, and miR-155/miR-34a antagomirs blocked stellate cell activation, confirming causality.

Clinical Implications

Although preclinical, targeting ATM phenotypes or their sEV miRNA cargo (e.g., miR-155/miR-34a) could represent novel anti-fibrotic strategies for MASH, complementing metabolic therapies.

Limitations

• Findings are in obese male mice; human validation is lacking.
• The specific dosing, kinetics, and safety of targeting sEV miRNAs were not evaluated clinically.

Future Directions

Validate ATM-sEV signatures and miR-155/miR-34a effects in human MASH, and develop targeted delivery or macrophage reprogramming approaches to modulate sEV cargo.