title: 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.affiliation: *Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany †School of Allied Health Sciences and Public Health, Walailak University, Nakhon Si Thammarat, Thailand.
authors.forename: Tanyarath
authors.initials: T
authors.lastname: Utaipan
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Otto
authors.forename: Hongying
authors.initials: H
authors.lastname: Gan-Schreier
authors.forename: Warangkana
authors.initials: W
authors.lastname: Chunglok
authors.forename: Anita
authors.initials: A
authors.lastname: Pathil
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008246:Lysophospholipids; D019014:fas Receptor; C000598975:ursodeoxycholyl lysophosphatidylethanolamide; D014580:Ursodeoxycholic Acid