Loss of endothelial ZEB2 in mice attenuates steatosis early during metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, features liver sinusoidal endothelial cell (LSEC) alterations with ill-defined driving factors. Zinc-Finger E-Box-binding Homeobox (ZEB)2 in LSECs preserves their specialized features, prevents capillarization and protects against liver fibrosis. To investigate a potential protective role against steatosis, the initial MASLD stage, we fed EC-specific Zeb2 knockout (EC) mice a western-type diet (WD). In healthy and steatotic wild-type livers, Zeb2 was ubiquitously and similarly expressed across blood-vascular EC types. LSEC RNA sequencing revealed ZEB2 deficiency-triggered expression changes greatly overlapping with those evoked by WD-feeding. Endothelial ZEB2-loss and WD-feeding interacted to boost capillarization and fat metabolism, shown by increased expression of continuous EC markers and peroxisome proliferator-activated receptor (PPAR)α signaling components, respectively. Altered communication among LSECs after combined endothelial ZEB2-loss and WD-exposure revealed similar functional repercussions. Endothelial ZEB2-loss eventually corrected WD-induced liver hypo-vascularization while ameliorating hepatic damage and steatosis. Thus, endothelial ZEB2-loss amplifies WD-induced LSEC fat metabolism and capillarization, while decreasing steatosis, in part through altered LSEC-LSEC communication. The disease-promoting role of endothelial ZEB2 in early MASLD as opposed to its protective role in fibrosis underscores a context-dependent effect in liver disease.