title: Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins.
abstract: An increase of toxic bile acids such as glycochenodeoxycholic acid occurs during warm ischemia reperfusion causing cholestasis and damage in hepatocytes and intrahepatic biliary epithelial cells. We aim to test antiapoptosis effects of ursodeoxycholyl lysophosphatidylethanolamide under cholestatic induction by glycochenodeoxycholic acid treatment of mouse hepatocytes and hypoxia induction by cobalt chloride treatment of intrahepatic biliary epithelial cancer Mz-ChA-1cell line. Such treatments caused marked increases in apoptosis as evidenced by activation of caspase 3, caspase 8 and poly (ADP-ribose) polymerase-1. Co-treatment with ursodeoxycholyl lysophosphatidylethanolamide significantly inhibited these increases. Interestingly, ursodeoxycholyl lysophosphatidylethanolamide was able to increase expression of antiapoptotic cellular FLICE-inhibitory protein in both cell types. Ursodeoxycholyl lysophosphatidylethanolamide also prevented the decreases of myeloid cell leukemia sequence-1 protein in both experimental systems, and this protection was due to ursodeoxycholyl lysophosphatidylethanolamide's ability to inhibit ubiquitination-mediated degradation of myeloid cell leukemia sequence-1, and to increase the phosphorylation of GSK-3β. In addition, ursodeoxycholyl lysophosphatidylethanolamide was able to prevent the decreased expression of another antiapoptotic cellular inhibitor of apoptosis 2 in cobalt chloride-treated Mz-ChA-1 cells. Hence, ursodeoxycholyl lysophosphatidylethanolamide mediated cytoprotection against apoptosis during toxic bile-acid and ischemic stresses by a mechanism involving accumulation of cellular FLICE-inhibitory protein, myeloid cell leukemia sequence-1 and cellular inhibitor of apoptosis 2 proteins. Ursodeoxycholyl lysophosphatidylethanolamide may thus be used as an agent to prevent hepatic ischemia reperfusion.
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Myra
authors.initials: M
authors.lastname: Sellinger
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Pathil
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, University Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Walee.Chamulitrat@med.uni-heidelberg.de.
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D005999:Glycochenodeoxycholic Acid / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; D005999:Glycochenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Bile acid toxicity; antiapoptosis proteins; cytoprotective drug; hypoxia; proteasome-mediated degradation