FNDC4 regulates TGF-β1-induced hepatic stellate cell activation and liver fibrosis via the AMPK/YAP pathway.

BACKGROUND & AIMS: Fibronectin type III domain-containing 4 (FNDC4) protein regulates hepatocyte insulin sensitivity, mitochondrial homeostasis, and inflammation. We investigated in vitro and ex vivo whether hepatocyte-derived FNDC4 limits transforming growth factor-β1 (TGF-β1)-driven hepatic stellate cell (HSC) activation and fibrogenesis, contributing to attenuate liver fibrosis in obesity-associated metabolic dysfunction-associated steatotic liver disease (MASLD).

METHODS

Plasma (n = 200) and hepatic expression (n = 75) of FNDC4 together with liver fibrosis were determined in participants with severe obesity and available liver pathology analysis. The effects of FNDC4 on HSC activation, fibrogenesis, and migration triggered by TGF-β1 were examined in vitro using human LX-2 HSCs.

RESULTS

Circulating and hepatic expression levels of FNDC4 were inversely correlated with liver fibrosis severity. FNDC4 was predominantly expressed in hepatocytes, not in HSCs, and localized to regions adjacent to fibrosis. In HSCs, FNDC4 treatment enhanced basal transdifferentiation into myoblast-like cells, increasing mitochondrial activity and glycolysis, key features of HSC activation. Mechanistically, AMPKα played a crucial role in FNDC4-induced elevation of mitochondrial DNA and mitochondrial network-regulating genes. Under TGF-β1 stimulation, FNDC4 selectively attenuated HSC collagen type I expression, apoptosis and ROS production, while concurrently increasing MMP-1, a key collagen-degrading enzyme, and GATA4, a transcription factor linked to cell deactivation. FNDC4 also inhibited TGF-β1-induced HSC migration by suppressing YAP expression and activation, a downstream target of AMPK.

CONCLUSIONS

Hepatocyte-derived FNDC4 functions as an anti-fibrogenic factor by modulating HSC activation and suppressing TGF-β1-driven fibrogenesis and migration via the AMPK/YAP pathway. Reduced hepatic FNDC4 may contribute to persistent liver fibrosis in obesity-related MASLD.