Endoplasmic reticulum (ER) stress is considered as a key factor in free fatty acid (FFA)-induced apoptosis. ERp46, a new member of the thioredoxin family, is highly expressed in pancreatic beta-cells and plays an important role in glucose toxicity. In this study we examined the potential role of ERp46 in palmitic acid (PA)-induced cell apoptosis and the protective role of exendin-4, a long-acting agonist of the hormone glucagon-like peptide-1 (GLP-1) receptor. The glucose-sensitive mouse beta-pancreatic cell line, beta TC6, was used to investigate the mechanisms of PA-induced apoptosis. Our results showed that ERp46 expression was reduced in a dose- and time-dependent manner after PA treatment. Furthermore, inhibition of ERp46 expression by small interfering (si)RNA-mediated silencing enhanced the ER stress response via three separate pathways and increased beta TC6 cell apoptosis rates. Moreover, exendin-4 reduced the ER stress response and levels of apoptosis in NC transfected cells after PA treatment, but not in cells transfected with ERp465iRNA. In conclusion, ERp46 plays a protective role in PA-induced cell apoptosis by decreasing the ER stress response and might be a novel target for anti-diabetic drugs. Exendin-4 might protect against beta TC6 cell lipoapoptosis in part by activating ERp46 signaling pathway. (c) 2012 Elsevier Inc. All rights reserved.