Endothelial cell LGR4 maintains liver sinusoidal endothelial cell Identity and protects against hepatic steatosis

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver pathological condition, develops due to complex interactions among various hepatic cell types. Emerging evidence demonstrates the pivotal role of hepatic endothelium, specifically the liver sinusoidal endothelial cell (LSEC) phenotype, in MASLD pathogenesis. While global ablation of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) improved metabolic fitness in mice, its cell-specific deletion revealed differential phenotypes. Here, we investigated the endothelial cell (EC)-specific role of Lgr4 in regulating LSEC phenotype and MASLD development.

Control and EC-specific Lgr4 knockout mice were used. Mice were analyzed for metabolic parameters, LSEC phenotype, hepatic steatosis, and potential underlying mechanisms, following Western diet feeding.

Male EC Lgr4-deficient mice exhibited metabolic dysfunction as indicated by increased weight gain, fat mass, fasting blood glucose, and plasma triglycerides. Consistent with increased liver weight, male mice with EC Lgr4 deletion exhibited exacerbated hepatic steatosis and upregulated mRNA levels of scavenger receptors Cd36 and Olr1. However, no differences in fibrosis marker anti-smooth muscle actin were observed. Notably, immunostaining experiments demonstrated enhanced LSEC capillarization, evidenced by reduced LYVE-1 and increased EMCN expression in the livers of EC-restricted Lgr4 knockout mice compared with controls, which was accompanied by increased hepatic inflammation. Similarly, female EC-specific Lgr4-deficient mice had increased hepatic steatosis. Mechanistically, loss of EC Lgr4 in mice promoted expression of apoptotic markers and suppressed AMPK activation.

These findings identify EC Lgr4 as an important regulator of hepatic lipid metabolism, LSEC capillarization, and MASLD progression.