title: The synthetic bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide suppresses TNFα-induced liver injury.
abstract: OBJECTIVE
  Excessive apoptosis and leukocyte-dependent inflammation mediated by pro-inflammatory cytokines, such as TNFα, are cardinal features of acute liver injury. This study evaluated the ability of the newly designed bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) to protect from hepatocellular injury in comparison to the known hepatoprotectant ursodeoxycholic acid (UDCA) and phosphatidylcholine (PC).
  
  
  METHODS
  Anti-apoptotic and anti-inflammatory properties of UDCA-LPE were evaluated after TNFα treatment of embryonic human hepatocyte cell line CL48 as well as of primary human hepatocytes. Acute liver injury was induced in C57BL/6 mice with d-galactosamine/lipopolysaccharide (GalN/LPS) in order to determine in vivo efficacy of the conjugate.
  
  
  RESULTS
  UDCA-LPE inhibited TNFα-induced apoptosis and inflammation in hepatocytes in vitro and markedly ameliorated GalN/LPS-mediated fulminant hepatitis in mice, whereas UDCA or PC failed to show protection. The conjugate was able to decrease injury-induced elevation of phospholipase A(2) activity as well as its product lysophosphatidylcholine. Analysis of hepatic gene expression showed that UDCA-LPE treatment led to favourable inhibitory effects on expression profiles of key pro-inflammatory cytokines and chemokines, which are crucial for leukocyte recruitment and activation thereby inhibiting chemokine-mediated aggravation of parenchymal damage.
  
  
  CONCLUSIONS
  Thus, UDCA-LPE as a synthetic bile acid-phospholipid conjugate may represent a potent anti-inflammatory agent that is more effective than UDCA and PC for treatment of liver diseases.
authors.affiliation: Department of Internal Medicine IV, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Pathil
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D005688:Galactosamine / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002756:Cholagogues and Choleretics; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; C008301:lysophosphatidylethanolamine; D014580:Ursodeoxycholic Acid; D005688:Galactosamine; D054467:Phospholipases A2