Differential effects of saturated and unsaturated free fatty acids on ferroptosis in rat ,?-cells

Elevated plasma concentrations of saturated free fatty acids (SFAs) are involved in pancreatic ,B-cell dysfunction and apoptosis, referred to as lipotoxicity. However, in contrast to apoptosis, the involvement of ferroptosis, as a distinct type of oxidative regulated cell death in ,B-cell lipotoxicity remains elusive. Therefore, the aim of this study was to determine the effects of various free fatty acids on ferroptosis induction in rat insulin-producing ,B-cells. Herein, rat insulin-producing , beta-cells underwent lipid peroxidation in the presence of long-chain SFAs and w-6-polyunsaturated fatty acids (PUFAs), but only the latter induced ferroptosis. On the other hand, the w-3-PUFA a-linolenate did not induce ferroptosis but sensitized insulin-producing ,B-cells to SFA-mediated lipid peroxidation. While the monounsaturated fatty acid oleate, overexpression of glutathione peroxidase 4, and the specific ferroptosis inhibitor ferrostatin-1 significantly abrogated lipid peroxidation, neither glutathione peroxidase 4 nor ferrostatin-1 affected palmitate-mediated toxicity. Site-specific expression of catalase in cytosol, mitochondria, and ER attenuated lipid peroxidation, indicating the contribution of metabolically generated H2O2 from all three sub-cellular compartments. These observations suggest that only w-6-PUFAs reach the thresholds of lipid peroxidation required for ferroptosis, whereas SFAs favour apoptosis in , beta-cells. Hence, avoiding an excessive dietary intake of w-6-PUFAs might be a crucial prerequisite for prevention of reactive oxygen species-mediated ferroptosis in insulin-producing cells. (C)& nbsp;2022 Elsevier Inc. All rights reserved.

Automated summary

Elevated concentrations of saturated free fatty acids (SFAs) are linked to dysfunction and apoptosis of pancreatic beta-cells. This study found that only ω-6 polyunsaturated fatty acids (PUFAs) induce ferroptosis, while the ω-3 PUFA α-linolenate sensitizes beta-cells to SFA-mediated lipid peroxidation. The prevention of excessive dietary intake of ω-6 PUFAs may be crucial in protecting insulin-producing cells from reactive oxygen species-mediated ferroptosis.