Ursodeoxycholyl lysophosphatidylethanolamide protects against CD95/FAS-induced fulminant hepatitis
ABSTRACT: Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the s...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
2017/08/01
|
| In: |
Shock
Year: 2017, Volume: 48, Issue: 2, Pages: 251-259 |
| ISSN: | 1540-0514 |
| DOI: | 10.1097/SHK.0000000000000831 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1097/SHK.0000000000000831 Verlag, Volltext: https://journals.lww.com/shockjournal/fulltext/2017/08000/Ursodeoxycholyl_Lysophosphatidylethanolamide.14.aspx 
|
| Author Notes: | Tanyarath Utaipan, Ann-Christin Otto, Hongying Gan-Schreier, Warangkana Chunglok, Anita Pathil, Wolfgang Stremmel, and Walee Chamulitrat |
| Summary: | ABSTRACT: Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis. |
|---|---|
| Item Description: | Gesehen am 31.10.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1540-0514 |
| DOI: | 10.1097/SHK.0000000000000831 |