Protective functions of the bile acid phospholipid conjugate Ursodeoxycholyl Lysophosphatidylethanolamide (UDCA-LPE) during hepatofibrogenesis

• Applicant: Privatdozentin Dr. Anita Pathil-Warth
• Subject Area: Gastroenterology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236740732

Liver fibrosis generally evolves from persisting inflammatory conditions of the liver. With increasing incidence of chronic inflammatory liver diseases such as non-alcoholic fatty disease (NAFLD), new therapeutic approaches to prevent fibrotic progression are urgently needed. As inflammation is the fuel perpetuating fibrogenesis, new anti-fibrogenic compounds capable of dampening inflammatory response within the liver in addition to the ability to inhibit ECM deposition would be desirable. Based upon the anti-inflammatory properties of certain phospholipids such as phosphatidylcholine the bile acid phospholipid conjugate Ursodeoxycholyl Lysophosphatidylethanolamide (UDCA-LPE) was designed in our group as a novel hepatoprotective agent. Our previous work revealed profound anti-apoptotic and anti-inflammatory properties of UDCA-LPE against TNF-induced cytotoxicity in vitro and further confirmed hepatoprotective functions in mouse models of endotoxin-mediated fulminant hepatitis and non-alcoholic fatty liver disease (NAFLD) in vivo. In this DFG application, we aim to characterize anti-fibrogenic functions of UDCA-LPE and its influence on pro-fibrogenic signalling pathways during hepatofibrogenesis. In our preliminary work we confirmed anti-fibrogenic functions of the conjugate in experimental models of stellate cell activation in LX2 cells, as well as in a mouse model of advanced non-alcoholic steatohepatitis with fibrosis due to long-term MCD diet. Thus, we now pursue to verify our results in primary human hepatic stellate cells and we aim to study the mechanisms contributing to an inhibition of TGF-mediated signal transduction especially regarding the suppressed phosphorylation of Smad3 and Smad2 due to UDCA-LPE. Moreover, besides the influence of the conjugate on hepatic stellate cells the effect of UDCA-LPE on TGF-mediated epithelial-to-mesenchymal transition (EMT) will be analyzed in primary mouse hepatocytes. Our preliminary data showed profound anti-inflammatory properties of UDCA-LPE due to the ability of the compound to inhibit the secretion of pro-inflammatory cyto- and chemokines by macrophages. Thus, we aim to study the suppression of inflammatory mediators by UDCA-LPE with respect to its impact on signalling pathways like e.g. the Interleukin-6/pStat3 pathway, which is supposed to play an important role during hepatofibrogenesis. Furthermore, protective functions of UDCA-LPE will be analyzed in a mouse model of NASH-induced fibrosis and hepatocarcinogenesis in vivo. The results will help to define a precise anti-fibrogenic profile of UDCA-LPE with respect to potential therapeutic applications of the conjugate for the prevention of fibrogenic progression of chronic liver disease.

• DFG Programme: Research Grants
• Participating Person: Walee Chamulitrat, Ph.D.