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) 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. 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. 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. • Plasma and hepatic FNDC4 expression are reduced in patients with liver fibrosis. • FNDC4 activates hepatic stellate cells (HSCs), promoting a myofibroblast-like phenotype and enhancing mitochondrial activity and glycolysis. • In TGF-β1-stimulated HSCs, FNDC4 decreases apoptosis and upregulates GATA4, a key transcription factor involved in HSC deactivation. • FNDC4 attenuates TGF-β1-induced fibrogenic and migratory responses via AMPK/YAP signaling pathways in HSCs.
Neira et al. (Sun,) studied this question.