Ursodeoxycholyl Lysophosphatidylethanolamide (UDCA-LPE) Protects Mouse Hepatocytes from Lipoapoptosis by Upregulating Stearoyl-CoA Desaturase-1

Introduction: We had previously shown that UDCA-LPE induced activation of cell survival PI3K/Akt and ERK1/2 pathways, and inhibited TNF-alpha-induced apoptosis in hepatocyte cell lines. Our goals are to demonstrate protective role of UDCA-LPE from lipotoxicity in primary mouse hepatocytes, and to delineate mechanism of action involving G-protein coupled receptor (GPCR) and the synthesis of triglycerides (TG) that are known to divert saturated fatty acids away from apoptosis. The latter involves stearoyl-CoA desaturase-1 (SCD1). Methods: Primary hepatocytes were prepared from C57/BL6 mice. Active Galphai-GPCR and SCD-1 were measured by immunoblotting. Palmitate (Pal) was used to induce apoptosis. Intracellular cAMP, non-esterified fatty acids (NEFA), and TG were measured using kits. Results: We showed that UDCA-LPE induced increases of active Galphai-GPCR leading to increased intracellular cAMP. Consistently, downstream activation of Akt and ERK1/2 induced by UDCA-LPE was inhibited by Galphai inhibitor Pertussis toxin. Time course study revealed that treatment of cells with UDCA-LPE or 8-bromo-cAMP caused increases of NEFA and TG levels at 9h (which were inhibitable by Pertussis toxin) and returned back to control levels at 20h. This transient de novo lipogenesis was associated with an induction of SCD-1 protein by UDCA-LPE in a similar manner as oleate, palmitoleate or 8-bromo-cAMP. Upon co-treatment with Pal for 20h, UDCA-LPE markedly inhibited Pal-induced apoptosis, and concomitantly further increased intracellular TG levels compared to Pal alone. Effects of UDCA-LPE on SCD-1 activity are being investigated. Discussion/Conclusion: UDCA-LPE’s ability to upregulate SCD-1 and increase TG may represent a mechanism to protect hepatocytes from lipoapoptosis. Since SCD-1 is an important metabolic control point in lipid metabolism as well as apoptosis inhibition, this targeting of SCD-1 may render UDCA-LPE as a therapeutic agent for treatment of steatohepatitis.

Hepatoprotection - NASH - lipid metabolism - triglycerides