Liver endothelial zonation orchestrates MASLD onset via retinoic acid-regulated FGF1 signaling

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic, often progressing to cirrhosis. Current therapies are limited, highlighting an urgent need for novel mechanistic insights and interventions. While hepatocytes are central to lipid metabolism, the contribution of liver sinusoidal endothelial cell (LSEC) zonation – the functional specialization of LSECs along the liver sinusoid – to MASLD pathogenesis has been largely undefined. Understanding how these distinct LSEC populations influence local metabolic environments could unlock new therapeutic avenues by targeting specific cellular interactions and signaling pathways that regulate hepatic steatosis.

Researchers investigated the role of liver sinusoidal endothelial cell (LSEC) zonation in early MASLD development. They first identified selective lipid deposition patterns within the liver's pericentral zone. To elucidate the underlying mechanisms, multiomics analyses were performed on both hepatocytes and LSECs to characterize lipid metabolism profiles across different zones. Mechanistic studies focused on identifying key regulatory molecules and pathways within pericentral LSECs. Finally, clinical data were analyzed to explore correlations between dietary vitamin A intake and MASLD severity, providing translational context for their preclinical findings.

The study revealed selective lipid deposition occurring predominantly in the pericentral zone during early MASLD onset. Multiomics analyses confirmed enhanced lipid metabolism in both pericentral hepatocytes and LSECs, indicating a coordinated zonal response. Mechanistically, the pericentral LSEC marker c-Kit was found to transcriptionally activate FGF1 expression through the nuclear receptor RXRG. This RXRG-mediated FGF1 activation subsequently suppressed hepatocellular lipid accumulation via activation of FGFR4 signaling. This establishes a critical LSEC-hepatocyte crosstalk pathway. > Retinoic acid, the endogenous ligand for RXRG and an active vitamin A metabolite, effectively phenocopied FGF1's antisteatotic effects, directly linking vitamin A to this protective mechanism. Clinical data further supported these findings, showing an inverse correlation between dietary vitamin A intake and MASLD severity, suggesting its potential as a therapeutic strategy.