Abstract
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of non-alcoholic steatohepatitis (NASH). We herein 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 adenosine 3', 5'-cyclic monophosphate (cAMP), and was associated with increases of triglycerides (TG) and phospholipids (PL). An inhibitor of cAMP-effector protein kinase A partially reversed protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to mono- 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 channelling 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 towards 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 TG and PL, and the latter may protect lipotoxicity at the membrane levels.
- The American Society for Pharmacology and Experimental Therapeutics