title: Ursodeoxycholyl lysophosphatidylethanolamide inhibits lipoapoptosis by shifting fatty acid pools toward monosaturated and polyunsaturated fatty acids in mouse hepatocytes.
abstract: Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of nonalcoholic steatohepatitis (NASH). We studied the ability of UDCA-LPE to inhibit palmitate (Pal)-induced apoptosis in primary hepatocytes and delineate cytoprotective mechanisms. We showed that lipoprotection by UDCA-LPE was mediated by cAMP and was associated with increases in triglycerides (TGs) and phospholipids (PLs). An inhibitor of cAMP-effector protein kinase A partially reversed the protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to monounsaturated and polyunsaturated fatty acids, mainly, oleate, docosapentaenoate, and docosahexaenoate. The latter two ω-3 fatty acids were particularly found in phosphatidylcholine and phosphatidylserine pools. The catalysis of Pal by stearoyl-CoA desaturase-1 (SCD-1) is a known mechanism for the channeling of Pal away from apoptosis. SCD-1 protein was upregulated during UDCA-LPE lipoprotection. SCD-1 knockdown of Pal-treated cells showed further increased apoptosis, and the extent of UDCA-LPE protection was reduced. Thus, the major mechanism of UDCA-LPE lipoprotection involved a metabolic shift from toxic saturated toward cytoprotective unsaturated fatty acids in part via SCD-1. UDCA-LPE may thus be a therapeutic agent for treatment of NASH by altering distinct pools of fatty acids for storage into TGs and PLs, and the latter may protect lipotoxicity at the membrane levels.
authors: Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, Im Neuenheimer Feld, Heidelberg, Germany (W.C., H.G.-S., A.P., W.S.); Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany (G.L., G.S.); and Department of Gastroenterology, Hangzhou First People's Hospital, Hangzhou, Zhejiang, People's Republic of China (W.X.).
authors: Walee
authors: W
authors: Chamulitrat
authors: Gerhard
authors: G
authors: Liebisch
authors: Weihong
authors: W
authors: Xu
authors: Hongying
authors: H
authors: Gan-Schreier
authors: Anita
authors: A
authors: Pathil
authors: Gerd
authors: G
authors: Schmitz
authors: Wolfgang
authors: W
authors: Stremmel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000242:Cyclic AMP / Q000502:physiology; D019610:Cytoprotection; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013230:Stearoyl-CoA Desaturase / Q000502:physiology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D005227:Fatty Acids; D008246:Lysophospholipids; C008301:lysophosphatidylethanolamine; D014580:Ursodeoxycholic Acid; D000242:Cyclic AMP; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase