Different functions of vitamin E homologues in the various types of cell death induced by oxysterols

24(S)-Hydroxycholesterol (24S-OHC) and 25-hydroxycholesterol (25-OHC) are produced by cholesterol 24-hydroxylase and cholesterol 25-hydroxylase, respectively. The purpose of the present study was to determine the type of cell death induced by these oxysterols in neuronal cells, hepatic cells, and keratinocytes, and to elucidate the inhibitory effect of vitamin E homologues on various types of cell death. In human neuronal cells (SH-SY5Y cells), 24S-OHC and 25-OHC caused a cell death that was independent of caspase activation. We reported previously that the esterification of 24S-OHC by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and the resulting formation of a lipid droplet (LD)-like structure are responsible for the 24S-OHC-induced neuronal cell death. Here, we found that 25-OHC also induced ACAT1-mediated 25-OHC esterification and LD formation in neuronal cells. 25-OHC-induced cell death was inhibited by alpha-tocopherol (alpha-Toc) but not by alpha-tocotrienol (alpha-Toc3), as observed for 24S-OHC-induced cell death in SH-SY5Y cells. In human hepatic cells (HepG2 cells), these oxysterols caused a cell death that was caspase-and oxysterol-esterification-independent. This cell death was suppressed by both alpha-Toc and alpha-Toc3, suggesting the involvement of free-radical-mediated lipid peroxidation in the cell death induced by these oxysterols in hepatic cells. In human keratinocytes (HaCaT cells), these oxysterols caused a caspase-dependent but oxysterol-esterification-independent cell death that was inhibited by alpha-Toc but not by alpha-Toc3. These results suggest that alpha-Toc and alpha-Toc3 act as radical-scavenging antioxidants against oxysterol-induced cell death in the same way in hepatic cells, whereas their behavior is different in inhibition of cell death in neuronal cells and keratinocytes. Collectively, these results demonstrated that 24S-OHC and 25OHC induced the same type of cell death in each of the cell types examined, and that alpha-Toc and alpha-Toc3 exerted different effects, depending on the type of cell death.

Automated summary

24S-OHC and 25OHC induced the same type of cell death in each of the cell types examined, and the inhibitory effect varied depending on the type of cell death for alpha-Toc and alpha-Toc3.