Expression and regulation of liver regeneration associated protein ALR under patho-physiological conditions
Year: 2010
Type: dissertation
Abstract: Liver regeneration is a multistep and well-orchestrated process which is initiated by injuries like tissue loss, infectious or toxic insults. It has been shown that expression of the hepatotrophic factor �Augmenter of Liver Regeneration� (ALR) is increased within liver regeneration as well as in liver diseases like cirrhosis and liver carcinoma. The aim of this thesis was to analyze how ALR is expressed, regulated and what impact an altered expression of ALR might have on the liver. Therefore, we investigated the expression of ALR in experimental models of liver injury which resemble hepatic patho-physiological disorders such as liver fibrosis and non-alcoholic steatohepatitis. ALR mRNA expression could be shown to be upregulated independent of different insults and is increased in HCC tissues compared to normal tissues. Furthermore, our results showed that IL-6 rapidly induces the mRNA expression and protein level of ALR in human hepatocytes and hepatoma cells, whereas IL-1 beta reduces the expression levels of ALR. No changes in ALR levels could be observed after stimulation with growth factors suggesting that ALR is regulated only by factors which are known to initiate the process of regeneration. Further, we analyzed the promoter sequence of ALR and identified putative regulatory elements for FOXA2, IL 6 RE BP and C/EBP beta. Using luciferase assays and EMSA, we demonstrated that both IL-6 RE-BP and C/EBP beta could not transactivate/bind to the ALR promoter. In contrast, FOXA2 has been found to regulate the expression of ALR, and this regulation was amplified by simultaneously activation using IL-6. Additionally, ALR promoter exhibits a nearly conserved Nrf2 binding site underlining a hepatoprotective function of ALR against oxidative stress. Using ALR overexpressing HepG2 cells we could not detect an altered proliferation rate neither in vitro nor in vivo. ALR-overexpressing cells displayed an enhanced acquirement to adhere and a significant lower ability to migrate and invade compared to wild type cells. Furthermore, we demonstrated that ALR expression induces the expression of the adhesion molecule E-cadherin and reduces the expression of MMP-3 and SNAIL explaining the modulation of E-cadherin by ALR. In conclusion, in this thesis was shown that ALR plays a role in hepatic regeneration independent of its cause and is regulated by upstream factors of liver regeneration like cytokines. Addionally, it was demonstrated that ALR expression counteracts the epithelial mesenchymal transition (EMT) suggesting that application of ALR represents a promising therapeutical strategy for diseases in which EMT is involved.
Author: Rania Dayoub
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W157842328