The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis.

Summary

Using an HSC-specific inducible transgenic system (Lrat-rtTA), the authors show that HSC ablation protects against MCD diet-induced fibrosis and that HSC-specific adiponectin overexpression suppresses, while deletion accelerates, fibrosis. They define a local adiponectin–PPARγ axis in HSCs that regulates fibrosis independently of circulating adiponectin.

Key Findings

• An HSC-specific, doxycycline-inducible Lrat-rtTA line enables precise gene manipulation in stellate cells.
• HSC ablation protects against MCD diet-induced fibrosis, confirming causal involvement of HSCs.
• HSC-specific adiponectin overexpression reduces, while deletion accelerates, fibrosis via a local adiponectin–PPARγ axis independent of circulating adiponectin.

Clinical Implications

Suggests potential for HSC-targeted PPARγ activation or enhancement of local adiponectin signaling in liver fibrosis, complementing systemic metabolic therapies for NASH/NAFLD.

Limitations

• Primarily MCD diet model; validation in additional fibrosis etiologies (e.g., toxic, cholestatic) is needed.
• Translational biomarkers linking HSC-local signaling to human fibrosis progression remain to be established.

Future Directions

Test HSC-targeted PPARγ modulators and enhance local adiponectin signaling in diverse fibrosis models; develop imaging/serologic biomarkers of HSC PPARγ activity for clinical translation.