The Role of Sirtuin 1 in Palmitic-acid-induced Endoplasmic-reticulum Stress in Cardiac Myoblasts
Abstract Background: Lipotoxicity causes endoplasmic reticulum (ER) stress, leading to cell apoptosis. Sirtuin 1 (Sirt1) regulates gene transcription and cellular metabolism. In this study, we investigated the role of Sirt1 in palmitate-induced ER stress. Methods: H9c2 myoblasts and heart-specific Sirt1 knockout mice fed a palmitate-enriched high-fat diet were used. Results: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt1 knockout mice and controls. Sirt1 knockout mice showed higher CHOP and ATF4 expression compared to those in control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. PA-treated H9c2 cells showed decreased cytosolic NAD+/NADH alongside reduced Sirt1’s activity. H9c2 cells showed increased ATF4 and CHOP expression when transfected with plasmid encoding dominant negative mutant Sirt1. Sirt1 activator SRT1720 did not affect CHOP and ATF4 expression. Although SRT1720 enhanced nuclear translocation of ATF4, the extent of the binding of ATF4 to the CHOP promoter did not increase further in PA treated-H9c2 cells.Conclusion: PA-induced ER stress is mediated through upregulation of ATF4 and CHOP. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt1 activity. The Sirt1 activator SRT1720 promotes nuclear translocation of ATF4 in PA-treated H9c2 cells.