OPN-Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH-Associated Liver Fibrosis

Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.