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Research ArticleArticle

Ursodeoxycholyl Lysophosphatidylethanolamide Inhibits Lipoapoptosis by Shifting Fatty Acid Pools toward Monosaturated and Polyunsaturated Fatty Acids in Mouse Hepatocytes

Walee Chamulitrat, Gerhard Liebisch, Weihong Xu, Hongying Gan-Schreier, Anita Pathil, Gerd Schmitz and Wolfgang Stremmel
Molecular Pharmacology November 2013, 84 (5) 696-709; DOI: https://doi.org/10.1124/mol.113.088039
Walee Chamulitrat
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.)
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Gerhard Liebisch
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.)
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Weihong Xu
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.)
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Hongying Gan-Schreier
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.)
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Anita Pathil
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.)
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Gerd Schmitz
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.)
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Wolfgang Stremmel
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.)
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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.

Footnotes

    • Received June 18, 2013.
    • Accepted August 23, 2013.
  • This work was supported by Deutsche Forschungsgemeinschaft [STR 216/15-3]; and European Community’s Seventh Framework Programme IP-Project Lipidomic Net [FP7/2007-2013-202272].

  • Part of this work was previously presented as a poster as follows: Chamulitrat W, Xu W, Katava N, Pathil A, and Stremmel W (2011) Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) evokes hepatoprotection via G-protein coupled receptors and by modulating desaturase gene expression. The European Association for the Study of the Liver; 2011 Mar 30–Apr 3; Berlin, Germany.

  • dx.doi.org/10.1124/mol.113.088039.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (5)
Molecular Pharmacology
Vol. 84, Issue 5
1 Nov 2013
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Research ArticleArticle

Lipoprotection by UDCA-LPE

Walee Chamulitrat, Gerhard Liebisch, Weihong Xu, Hongying Gan-Schreier, Anita Pathil, Gerd Schmitz and Wolfgang Stremmel
Molecular Pharmacology November 1, 2013, 84 (5) 696-709; DOI: https://doi.org/10.1124/mol.113.088039

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Research ArticleArticle

Lipoprotection by UDCA-LPE

Walee Chamulitrat, Gerhard Liebisch, Weihong Xu, Hongying Gan-Schreier, Anita Pathil, Gerd Schmitz and Wolfgang Stremmel
Molecular Pharmacology November 1, 2013, 84 (5) 696-709; DOI: https://doi.org/10.1124/mol.113.088039
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