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.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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