TY  - GEN
AV  - public
A1  - Wojtalla, Alexandra
ID  - heidok12718
N2  - Liver fibrosis is the response to chronic hepatic injury and results from an increased deposition of connective scar tissue by activated hepatic stellate cells (HSCs). Removal of activated HSCs preceded amelioration of fibrosis and can prevent further severe complications of chronic hepatic injury, which result in a high mortality rate worldwide. In this thesis it was shown the first time, that the endocannabinoids virodhamine, noladin ether and N-arachidonoyl dopamine (NADA) specifically induce cell death in HSCs but not in hepatocytes. Due to the selective expression of effective defence systems like antioxidants and the NADA degradation enzyme fatty acid amide hydrolase (FAAH), hepatocytes showed resistance to NADA-induced cell death. The synthesising enzyme of NADA was shown to be strongly expressed in hepatocytes but not in HSCs. Thus, NADA has therapeutic potential as an antifibrotic endogenous agent. Moreover, in a recent study it was shown that the endocannabinoid 2-arachidonoyl glycerol (2-AG) is strongly upregulated in the injured liver. In this thesis it is shown that elevated 2-AG levels during liver fibrogenesis are due to elevated expression of the 2-AG synthesising enzyme and decreased levels of the 2-AG degradation enzyme. The data further points to non-parenchymal cells rather than to hepatocytes being the most important cells in 2-AG metabolism in the liver. Recently it was shown that 2-AG specifically induces cell death in HScs but not in hepatocytes. HSCs and hepatocytes differentially express COX-2, leading to differential metabolism of 2-AG. The generation of pro-apoptotic PGD2-GE by COX-2 in HSCs possibly contributes to the different susceptibility of hepatocytes and HSCs towards 2-AG-induced cell death. In conclusion, the understanding of the role of endocannabinoid-mediated pathways in liver injury and fibrosis will make it possible to specifically target components of this system to decrease fibrogenesis.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/12718/
KW  - COX-2 
KW  -  Endocannabinoidsystemendocannabinoids 
KW  -  liver fibrosis
TI  - Liver fibrosis and endocannabinoids
Y1  - 2011///
ER  -