Glia maturation factor-β in hepatocytes enhances liver regeneration and mitigates steatosis and ballooning in zebrafish.

Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regeneration, hepatocyte-specific knockout (HepGKO) and overexpression (HepGOE) zebrafish strains were constructed. Both transgenic and wild-type (WT) zebrafish underwent partial hepatectomy (PHX) or were fed high-fat, high-cholesterol diets to model metabolism-associated steatotic liver disease (MASLD). Under physiological conditions, the HepGKO, HepGOE, and WT fish displayed similar survival, gross appearance, and liver histology. Following PHX, WT liver gmfb levels positively correlated with cell proliferation and proinflammatory cytokine levels. HepGOE showed enhanced regeneration and reduced liver steatosis compared with WT, whereas HepGKO exhibited opposite effects. In MASLD, WT liver gmfb increased with disease progression. HepGKO experienced worsening liver enlargement, steatosis, ballooning, inflammation, and endoplasmic reticulum stress, whereas HepGOE showed improvements. HepGOE liver had the highest cell proliferation, but all three groups showed similar levels of cell apoptosis. Moreover, elevated proinflammatory cytokines were observed across MASLD groups, being the highest in HepGKO and lowest in HepGOE. However, signal transducer and activator of transcription 3 (stat3) activation was the lowest in HepGKO and highest in HepGOE, whereas jnk and mapk/extracellularly regulated kinase (erk) activation was consistent across the MASLD groups. In il6-treated primary hepatocytes, gmfb abundance influenced stat3 activation, and hep-gmfb abundance significantly affected actin filaments distribution in hepatocytes both in vivo and vitro. Hep-Gmfb boosts regenerative processes by enhancing hepatocyte proliferation, alleviating fatty liver histological abnormalities, and modulating the Il6/Stat3 signaling, potentially through remodeling of actin-filament network within hepatocytes. Glia maturation factor-β (Gmfb) has shown important implications in liver disease. Using transgenic zebrafish models, our research demonstrates that Gmfb in hepatocytes confers protective benefits for liver regeneration and repair. It promotes hepatocyte proliferation, alleviates steatosis and ballooning, and modulates Il6/Stat3 signaling in response to liver injuries, potentially through remodeling of actin-filament network. This submission represents the first in vivo observation of the phenotypic effects of Gmfb in hepatocytes during liver injury.