title: Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish.
abstract: Alcoholic liver disease (ALD) results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF) and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the zebrafish model to identify molecular targets for developing ALD therapies.
authors: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Changwen
authors: C
authors: Zhang
authors: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Jillian L
authors: JL
authors: Ellis
authors: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA chunyue.yin@cchmc.org.|Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Chunyue
authors: 0000-0002-3784-6363
authors: C
authors: Yin
mesh_terms: D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D000431:Ethanol; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007814:Larva / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C575425:(4-(4'-chloro-2'-fluoro)phenylamino)-6,7-dimethylquinazoline; D016326:Extracellular Matrix Proteins; D008024:Ligands; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; D000431:Ethanol; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Angiogenesis; Fibrogenesis; Hepatic stellate cells; Kdrl; Steatosis; VEGF