Der Einfluss von Endoglin auf die Fibrose, sowie die Inflammation und Regeneration in der Leber

  • The Impact of Endoglin on Fibrosis, as well as Inflammation and Regeneration in the Liver

Sterzer, Viktor; Schirawski, Jan (Thesis advisor); Ludwig, Andreas (Thesis advisor)

Aachen (2017)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2017

Abstract

The aim of this thesis was to investigate the impact of endoglin (Eng), an auxiliary transforming growth factor beta (TGF-β) receptor on liver sinusoidal endothelial cells (LSECs) on the liver fibrosis development. Additionally the impact of endoglin on liver regeneration and -inflammation in mice was investigated. Furthermore the role of endoglin in the setting of nonalcoholic steatohepatitis (NASH) as well as a nonalcoholic fat liver disease (NAFLD) combined with an hepatocellular carcinoma (HCC) in human liver biopsies should be elucidated. Methods: In the fibrosis models Mice with an LSEC specific Eng knockout were injected with carbon tetrachloride (CCl4) or a bile duct ligation (BDL) was performed. In the liver regeneration and -Inflammation experiments mice with an ubiquitary Eng knockout were used. The liver regeneration was investigated with a 2/3 partial hepatectomy model (p. H.), while the 1/3 ischemia-Reperfusion (I-R) technique was used as a model for inflammation.Results: No differences could be observed in the fibrosis grade between knockout and control animals in the CCl4 as well as in the BDL model. Furthermore no differences in the liver to bodyweight ratio in the p. H. model were detectable. However, a trend to a higher proliferation and a reduced triglyceride concentration as well as a significant downregulation in the expression of the fat transport proteins Fatp5 and Fabp1in the knockout animals could be detected. In the I-R model slight differences in the leukocyte infiltration but no differences in the expression of inflammatory markers could be observed. The analysis of the human liver biopsies revealed a significant upregulation in the gene expression of ENG, SERPINE-1 and ID1 in NASH patients.In the NAFLD/HCC group a significant correlation between the expression of Eng and the genes IFNG, TNF, CXCL16, TGFB, COL1A1, TIMP, GLI2, CD74, CXCR4 and IL4 could be detected. There was no correlation between Eng and the degree of steatosis in clinically inconspicuous individuals.Conclusion: LSEC specific expression of endoglin has neither an impact on the fibrosis development in a CCl4 or BDL model respectively, nor has an ubiquitary endoglin knockout an influence on the hepatic inflammation or leukocyte infiltration in an I-R model. Hepatic steatosis in humans does not correlate with the endoglin expression, however endoglin could be involved in the cell proliferation and fat transport processes according to the results obtained in the p. H. experiments. The results of the human liver biopsy gene expression analysis allow the suggestion that endoglin could be involved in the development of NASH as well as HCC. To fully unravel the role of endoglin in these contexts further investigations are needed.