α-Tocopherol suppresses 24(S)-hydroxycholesterol-induced cell death via inhibition of endoplasmic reticulum membrane disruption

Abstract

The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24S-OHC) has been shown to cause neuronal cell death when subjected to esterification by acyl-CoA:cholesterol acyltransferase 1 (ACAT1). Accumulating 24S-OHC esters in the endoplasmic reticulum (ER) provoked ER membrane disruption and an integrated stress response (ISR), a signaling pathway that regulates adaptation to various stresses. We have previously reported that α-tocopherol (α-Toc) but not α-tocotrienol (α-Toc3), among vitamin E homologs, suppressed 24S-OHC-induced cell death without affecting ACAT1 activity in human neuroblastoma SH-SY5Y cells. However, the precise mechanisms underlying the inhibitory activity of α-Toc have yet to be elucidated. In the present study, we aimed to investigate the effects of α-Toc on the 24S-OHC-induced cell death machinery. We showed that α-Toc, but not α Toc3, suppressed 24S-OHC-induced ISR and downstream eukaryotic translation initiator factor 2α (eIF2α) phosphorylation. We also found that α-Toc inhibited stress granule formation and robust downregulation of nascent protein synthesis, which were induced by 24S-OHC treatment. Furthermore, disruption of ER membrane integrity was suppressed by α-Toc, but not by α-Toc3. Our findings suggest that the inhibitory effects of α-Toc on 24S-OHC-induced cell death may be attributed to its protective function against ER membrane disruption.

Keywords: 24S-hydroxycholesterol; Cell death; Integrated stress response; Stress granules; Tocopherol; Tocotrienol.