381 Dll4 and Jagged-1 Provide Opposing Effects in Liver Fibrosis

Liu, Y.; Shen, Zhihua; Xu, MY; Meyer, C. J. L. M.; Muller, Arnaud; Munker, Stefan; Li, Q.; Ilkavets, Iryna; Stump, C. W.; Müllenbach, Roman; Zimmer, Vincent; Lammert, Frank; Mertens, PR; Li, J.; Li, Y.-M.; Lu, LG; Dooley, Steven; Weng, HL

doi:10.1016/s0168-8278(12)60394-8

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“…AGS is a multisystem congenital disorder clinically defined by cholestatic liver disease with intrahepatic ductal paucity, structural cardiac defects, ocular anomalies, vertebral body abnormalities, and characteristic facies [ 9 ]. Despite the development of ductal paucity, clinical signs of cholestasis often regress as patients approach school age, and there may not be progression to biliary fibrosis or cirrhosis [ 4 , 9 ].Therefore, further studies are necessary to confirm if intervention of Jagged1 signaling can improve liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in Jagged1 lead to Alagille syndrome (AGS). It is interesting that patients with AGS do not develop serious fibrotic disease despite the paucity of bile ducts and hence a potentially cholestatic phenotype [ 4 ]. Expression of Jagged1 and Dll4 mRNA is seen in normal and diseased liver tissue, whereas expression of Jagged2, Dll1, and Dll3 mRNA is undetectable [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

et al. 2017

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The role of the Notch ligand Jagged1 in hepatic fibrosis remains to be elucidated. In the current study, we investigated the role of Jagged1 in the activation of hepatic stellate cells (HSCs) and development of hepatic fibrosis in rats. In vitro, Jagged1 in HSCs was downregulated and upregulated by Jagged1 siRNA and pcDNA3.1 Jagged1, respectively. The levels of epithelial-mesenchymal transition (EMT) markers and HSC activation markers were assessed using western blot analysis. The proliferation and migration capacity of HSCs were assessed using 5-ethynyl-2′-deoxyuridine (EdU) incorporation and Transwell migration assays. In vivo, a recombinant adeno-associated virus type 1 (rAAV1) vector carrying Jagged1 shRNA (rAAV1-Jagged1-shRNA) was constructed and transferred to rat livers via the tail vein. Reversion of liver fibrosis and the effect of Jagged1 signaling on EMT were studied using pathological, immunohistochemical and immunofluorescence methods. Our findings revealed that downregulation and upregulation of Jagged1 inhibited and promoted, respectively, HSC activation. The migratory capacity of HSCs was markedly restrained by Jagged1 siRNA. Furthermore, downregulation of Jagged1 suppressed EMT in HSCs. rAAV1-Jagged1-shRNA was generated to treat CCl4-induced hepatic fibrosis in rats. Treatment with rAAV1-Jagged1-shRNA reversed hepatic fibrosis by decreasing EMT. The results of the present study suggest that inhibition of Jagged1 is a potential treatment to ameliorate liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%