Hepatology (Baltimore, Md.) · 2026
VPS13D protects against alcohol- associated steatohepatitis by regulating organelle contacts and VLDL secretion.
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Zhang Chen, Dunn Nicholas, Xie Yan, Davidson Nicholas O, Zhong Wei, Ding Wen-Xing, Ni Hong-Min
Аннотация
BACKGROUND: Organelle contact sites are critical for intracellular signaling, membrane dynamics, and organelle quality control. Here we examined the role of VPS13D, a bridge-like lipid transport protein, in alcohol-induced liver injury and defined the mechanisms by which VPS13D regulates lipid metabolism at organelle contact sites.
APPROACH AND RESULTS: Liver-specific Vps13d knockout (LKO) mice and matched wild-type (WT) mice were subjected to chronic-plus-binge ethanol feeding. RNA-seq and metabolomic analyses were performed to investigate changes in hepatic gene expression and metabolism. Biochemical, microscopic, and histological analyses were performed to examine organelle contacts and liver injury. Liver samples from patients with alcohol-associated hepatitis (AH) showed decreased VPS13D expression and mitochondrial-ER contact sites. Binge ethanol-fed Vps13d LKO mice developed more severe steatosis, inflammation and liver injury, with increased progenitor cells, compared with WT mice. Ethanol-fed Vps13d LKO mice exhibited decreased mitochondria-ER contact sites and peroxisome content, with increased lysosome damage and ER stress compared with WT mice. Metabolomic analysis revealed altered hepatic phospholipid homeostasis, with increased hepatic phosphatidylethanolamine (PE) and decreased phosphatidylcholine (PC) abundance, along with decreased phosphatidylethanolamine N-methyltransferase (PEMT) expression, resulting in impaired hepatic VLDL secretion in ethanol-fed Vps13d LKO mice. Adenovirus-mediated hepatic PEMT expression increased VLDL secretion and decreased steatosis and liver injury in ethanol-fed Vps13d LKO mice.
CONCLUSIONS: Loss of hepatic VPS13D disrupts mitochondria-ER contact sites, decreasing hepatic PC content and VLDL secretion, promoting ethanol-induced steatosis, progenitor cell accumulation, and liver injury. ER-mitochondrial contact disruption and altered phospholipid homeostasis may be pathogenic drivers in AH.
APPROACH AND RESULTS: Liver-specific Vps13d knockout (LKO) mice and matched wild-type (WT) mice were subjected to chronic-plus-binge ethanol feeding. RNA-seq and metabolomic analyses were performed to investigate changes in hepatic gene expression and metabolism. Biochemical, microscopic, and histological analyses were performed to examine organelle contacts and liver injury. Liver samples from patients with alcohol-associated hepatitis (AH) showed decreased VPS13D expression and mitochondrial-ER contact sites. Binge ethanol-fed Vps13d LKO mice developed more severe steatosis, inflammation and liver injury, with increased progenitor cells, compared with WT mice. Ethanol-fed Vps13d LKO mice exhibited decreased mitochondria-ER contact sites and peroxisome content, with increased lysosome damage and ER stress compared with WT mice. Metabolomic analysis revealed altered hepatic phospholipid homeostasis, with increased hepatic phosphatidylethanolamine (PE) and decreased phosphatidylcholine (PC) abundance, along with decreased phosphatidylethanolamine N-methyltransferase (PEMT) expression, resulting in impaired hepatic VLDL secretion in ethanol-fed Vps13d LKO mice. Adenovirus-mediated hepatic PEMT expression increased VLDL secretion and decreased steatosis and liver injury in ethanol-fed Vps13d LKO mice.
CONCLUSIONS: Loss of hepatic VPS13D disrupts mitochondria-ER contact sites, decreasing hepatic PC content and VLDL secretion, promoting ethanol-induced steatosis, progenitor cell accumulation, and liver injury. ER-mitochondrial contact disruption and altered phospholipid homeostasis may be pathogenic drivers in AH.