Liver Endothelial Heg1 Signal Limits Hepatic Steatosis via Wnt-Mediated Fatty Acid Oxidation in Hepatocytes

BACKGROUND & AIMS: Fatty liver diseases are highly prevalent worldwide, driven by hepatocyte metabolic dysfunction and alcohol consumption. Both cell-autonomous and non-cell-autonomous mechanisms contribute to hepatic lipid accumulation. Here, we investigated the role of liver endothelial cell-hepatocyte communication in regulating lipid metabolism. METHODS: ), in the context of 3 liver disease models: metabolic dysfunction-associated steatotic liver disease via a high-fat diet, metabolic dysfunction-associated steatohepatitis via a methionine-choline-deficient diet, and alcoholic liver disease via the National Institute on Alcohol Abuse and Alcoholism protocol. Subsequent transcriptomic and lipidomic analyses and tissue immunostainings were used to determine gene and protein expression levels and metabolic changes. RESULTS: EC-specific Heg1 deletion exacerbated hepatic steatosis under metabolic stress. Mechanistically, Heg1 deletion in liver endothelial cells downregulated bone morphogenetic protein signaling, leading to reduced expression of Wnt2, Wnt9b and Rspo3. This reduction attenuated Wnt signaling activation in hepatocytes, resulting in decreased expression of peroxisome proliferator-activated receptor α and fatty acid oxidation enzymes, ultimately promoting steatosis. Restoration of RSPO3 expression in endothelial cells via a conditional knock-in allele, reversed the steatotic phenotype. Treatment with bone morphogenetic protein proteins and SY-LB-35, a bone morphogenetic protein signaling activator, effectively restores RSPO3 expression. CONCLUSIONS: Heg1 functions as an essential endothelial receptor mediating liver endothelial-hepatocyte crosstalk. By sustaining endothelial Wnt production, Heg1 maintains hepatocyte peroxisome proliferator-activated receptor α activity and fatty acid oxidation, thereby preserving hepatic lipid homeostasis and protecting against steatosis.