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 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.

• Authors: Tanyarath Utaipan, Ann-Christin Otto, Hongying Gan-Schreier, Warangkana Chunglok, Anita Pathil, Wolfgang Stremmel, Walee Chamulitrat
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 48 Issue 2 Pg. 251-259 (08 2017) ISSN: 1540-0514 [Electronic] United States
• PMID: 28060213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Fas Ligand Protein
• Fasl protein, mouse
• Lysophospholipids
• fas Receptor
• ursodeoxycholyl lysophosphatidylethanolamide
• Ursodeoxycholic Acid

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Fas Ligand Protein (adverse effects, pharmacology)
• Gene Expression Regulation (drug effects)
• Liver (metabolism, pathology)
• Liver Failure, Acute (chemically induced, drug therapy, metabolism, pathology)
• Lysophospholipids (pharmacokinetics)
• Male
• Mice
• Ursodeoxycholic Acid (analogs & derivatives, pharmacokinetics)
• fas Receptor (metabolism)