Adipose tissue-derived MFG-E8 promotes hepatic inflammation and fibrosis through macrophage activation in a mouse MASH model.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatocellular injury, macrophage activation, and severe fibrosis, and often progresses to liver cirrhosis and hepatocellular carcinoma. Excessive accumulation of visceral fat exacerbates hepatic inflammation and fibrosis independently of fatty liver, but the underlying molecular mechanisms have remained unclear. We here identify MFG-E8 (milk fat globule-EGF8) as a secreted protein that is overexpressed in adipose tissue of obese mice and contributes to such exacerbation. MFG-E8 deficiency in MASH model (STAM-MASH) mice was associated with reduced hepatic expression of inflammation- and fibrosis-related genes without attenuation of steatosis. Conversely, MFG-E8 supplementation in MFG-E8 knockout mice intensified hepatic inflammation and promoted the formation of hepatic crownlike structures. Coculture of macrophages with apoptotic hepatocytes induced expression of inflammatory cytokine genes, and this effect was enhanced by the presence of exogenous MFG-E8 in the culture medium. Our findings suggest that adipose tissue-derived MFG-E8 infiltrates the liver and promotes macrophage-hepatocyte interaction, thereby contributing to hepatic inflammation and fibrosis in MASH.