Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612695
Poster Visit Session II Clinical Hepatology – Friday, January 26, 2018, 2:35pm – 3:20pm, Room 120
Georg Thieme Verlag KG Stuttgart · New York

Alcohol triggers IL-6 mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

E Karatayli
1   Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Homburg
,
R Hall
1   Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Homburg
,
S Weber
1   Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Homburg
,
S Dooley
2   Universität Heidelberg, Medizinische Fakultät, Mannheim
,
F Lammert
1   Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Homburg
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

 

Background and aims:

Altered host response to injury in the setting of a chronically damaged liver plays a critical role in development of acute-on-chronic liver injury, usually in the presence of an underlying precipitant. Here, we aim to combine a mouse model with pre-existing chronic liver injury (Abcb4/Mdr2-/-) with the recently standardized ethanol feeding model (NIAAA model, Nat Protoc 2013) to dissect alcohol-related inflammatory responses in this novel pre-clinical model.

Methods:

Ten (n = 64) and 15 (n = 64) week-old C57BL/6J and Mdr2-/- mice were either fed control (WT/Cont and MDR2/Cont groups) or liquid ethanol diet (5% v/v) followed by an acute ethanol binge (5 mg/kg) (WT/EtOH and MDR2/EtOH groups). Liver specific mRNA levels (relative to GAPDH) of IL-6, HGF, CRP and COL3A1 were evaluated using the 2-ΔΔCt method. ELISA was performed for IL-6 and HGF plasma. Hepatic collagen contents (hydroxyproline), plasma ALT, AST and AP as well as EtOH levels were measured. ANOVA followed by Bonferroni posthoc tests was performed.

Results:

Hydoxyproline and COL3A1 expressions were significantly higher in Mdr2-/- mice compared to controls and further increased by ethanol challenge. The older mice in MDR2/EtOH group displayed 2-, 3- and 4.1-fold higher IL-6 expressions vs. 15 week-old MDR2/Cont (p = 0.003), 15 week-old WT/EtOH (p < 0.001) and WT/Cont groups (p < 0.001), respectively. This elevation was more prominent in plasma, reaching a 10-fold increase (p < 0.0001) compared with 15 week-old WT/Cont group, whereas HGF did not differ. Hepatic CRP levels were significantly (p = 0.001) elevated in 15 week-old Mdr2-/- mice challenged with ethanol. Males in MDR2/EtOH group exhibited 1.7 (p = 0.011) and 2.1 (p < 0.001) fold higher IL6 and CRP expressions than females, respectively. Lipid droplets (LDs) in liver were observed in 80% of mice challenged with ethanol, regardless of whether they are wild-type or knock-out. There was a profound downregulation (p < 0.001) in Pnpla3 levels in these mice. The mean size of the LDs was inversely correlated with hepatic PNPLA3 levels.

Conclusions:

We propose a novel promising approach to model alcohol-related acute-on-chronic liver injury. We also speculate that acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Mdr2-/- mice, further increasing the known HCC risk in this model. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.

This study was supported by BMBF LiSyM project (031L0051) and HOMFOR2017 research fund (Saarland University)