Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis. Issue 2 (August 2017)

• Record Type: Journal Article
• Authors: Utaipan, Tanyarath; Otto, Ann-Christin; Gan-Schreier, Hongying; Chunglok, Warangkana; Pathil, Anita; Stremmel, Wolfgang; Chamulitrat, Walee
• Is Part Of: Shock. Volume 48:Issue 2(2017)
• Publication Date: 2017-08
• Subjects: Apoptosis -- CD95/Fas -- cytoprotective agent -- inflammation -- liver injury -- phospholipids -- ALT -- alanine transaminase -- AST -- aspartate transaminase -- CDS1 -- CDP-diacylglycerol synthase 1 -- cFLIP -- cellular FLICE-inhibitory protein -- ConA -- concanavalin A -- cPLA2 -- cytosolic phospholipase A2 -- DISC -- death-inducing signaling complex -- LDH -- lactate dehydrogenase -- LysoPC -- lysophosphatidylcholine -- LysoPE -- lysophosphatidyl-ethanolamine -- PAPR-1 -- poly (ADP-ribose) polymerase 1 -- PC -- phosphatidylcholine -- PE -- phosphatidylethanolamine -- qRT-PCR -- quantitative real-time PCR -- UDCA-LPE -- ursodeoxycholyl lysophosphatidylethanolamide; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000000831
• Languages: English
• ISSNs: 1073-2322

Abstract

Abstract : 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.