Liver endothelial Heg1 signal limits hepatic steatosis via Wnt-mediated fatty acid oxidization 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 three liver disease models: metabolic dysfunction-associated steatotic liver disease (MASLD) via high-fat diet (HFD), metabolic dysfunction-associated steatohepatitis (MASH) via methionine-choline-deficient diet (MCD), and alcoholic liver disease (ALD) via the National Institute on Alcohol Abuse and Alcoholism (NIAAA) 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 (BMP) 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 alpha (PPAR⍺) and fatty acid oxidation (FAO) enzymes, ultimately promoting steatosis. Restoration of RSPO3 expression in endothelial cells via a conditional knock-in allele, reversed the steatotic phenotype. Treatment with BMP proteins and SY-LB-35, a BMP 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 PPARα activity and FAO, thereby preserving hepatic lipid homeostasis and protecting against steatosis.