Z Gastroenterol 2019; 57(01): e1-e2
DOI: 10.1055/s-0038-1677067
Lectures Session 1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

Jagged-1 upregulation in stressed hepatocytes is crucial for liver regeneration

B Dewidar
1   Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
,
S Hammad
1   Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
3   Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
,
MP Ebert
1   Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
JG Hengstler
4   Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
,
S Dooley
1   Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Introduction:

Reactive oxygen species (ROS) initiate several liver diseases through DNA hydroxylation, lipid peroxidation, and protein adduct formation. In addition, ROS interacts with signaling pathways such as NOTCH1 and NRF2, which may have an impact on liver regeneration. In the current study, we report that the Notch ligand Jagged-1 (JAG1) is induced by ROS in hepatocytes and functionally investigate its role in liver repair processes.

Methods:

JAG1 expression and ROS were examined in (i) APAP/CCl4 animal models, (ii) mouse hepatocytes upon treatment with APAP and CCl4, and (iii) patients with HBV, alcoholic hepatitis (AH), and primary biliary cirrhosis (PBC). Involvement of Nrf2, ERK, and AKT signaling mechanisms was investigated through RNAi (Nrf2) and small molecule inhibitors U0126 and LY294002. JAG1 blocking antibody was used to functionally study the impact of JAG1 on liver regeneration in vivo. The impact of recombinant JAG1 (rJAG1) on phagocytic activity of RAW264.7 cells was studied in co-culture experiments with labeled hepatocyte debris.

Results:

JAG1 is expressed in hepatocytes surrounding the necrotic area following CCl4 and APAP administration to mice. APAP/CCl4 treatment also induced JAG1 expression in cultured mouse hepatocytes. ROS-stressed hepatocytes in HBV, AH, and PBC patients show high JAG1 expression. Activated NRF2 signaling and co-localization between JAG1 and SOD-2, Nrf2 downstream target, were obvious in APAP/CCl4-intoxicated animals. In vitro, APAP/CCl4-induced Jag1 expression is blunted by N-acetylcysteine, MAPK/ERK and PI3K/AKT inhibitors, but not by depleting Nrf2. However, diethyl maleate, NRF2 activator, dose-dependently increases JAG1 expression in HepG2 E47 cell line Similar to APAP. In vivo, inhibiting JAG1 by antibodies augments APAP-induced necrosis and apoptosis leading to delayed regeneration. Close contact between JAG1 expressing hepatocytes and macrophages is evident two days after CCl4/APAP-intoxication. In co-culture experiments, rJAG1 enhances phagocytic activity of macrophages, whereas the Notch inhibitor Dibenzazepine dampens this process.

Conclusion:

JAG1 expression in stressed hepatocytes is induced by ROS, MAPK/ERK, and PI3K/AKT dependent mechanisms, whereas the role of NRF2 is not yet robustly confirmed. Upregulated JAG1 facilitates liver regeneration by enhancing the phagocytic activity of restorative macrophages.