TY  - GEN
TI  - EGF/STAT1-maintained ECM1 expression in hepatic homeostasis is
disrupted by IFN?/NRF2 in chronic liver diseases
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/34387/
A1  - Li, Yujia
Y1  - 2024///
ID  - heidok34387
AV  - public
N2  - In healthy liver, L-TGF-? is stored in the extracellular matrix and stabilized in an inactive form by ECM1. Upon damage, ECM1 production is downregulated, especially in hepatocytes, leading to spontaneous L-TGF-? activation and fibrogenesis. I used in silico promoter analyses, performed in vitro studies in mouse/human hepatocytes and in vivo experiments with different mouse models, to mechanistically delineate maintenance versus downregulation of ECM1 expression under physiological and pathological conditions. I could identify the crosstalk of signaling pathways that maintain or inhibit ECM1 expression. 

In my thesis, I found that:
(1) In healthy liver, EGF and HGF are mediators of ECM1 expression maintenance. Thereby, EGF signals via EGFR/p-STAT1 S727 to the Ecm1 promoter. The HGF signal as well integrates at STAT1 signaling.
(2) Upon liver damage and injuries:
I. Inflammation-accumulated hepatic IFN? interferes with EGF signaling through downregulating EGFR. 
II. In addition, IFN? induces STAT1 phosphorylation at Y701, which interferes with binding of p-STAT1 S727 to the Ecm1 gene promoter. 
I and II together result in a decreased ECM1 expression.
III. Further, IFN? promotes NRF2 nuclear translocation, which binds to the Ecm1 gene promoter and negatively regulates its transcription, leading to inhibition of ECM1 expression. 
Taken together, the EGF/EGFR/p-STAT1 S727 pathway that maintains ECM1 expression homeostasis in healthy hepatocytes is disrupted and inhibited by inflammation-accumulated IFN? and its effects in stressed hepatocytes with the consequence of L-TGF-? activation and hepatic fibrosis. 

In conclusion, my findings delineate the regulation of ECM1 expression in hepatocytes, which has potential for therapeutic manipulation of its expression with impact on TGF-? availability to treat chronic liver diseases.
CY  - Heidelberg
ER  -