Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto, 610-0394, Japan.
Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto, 610-0394, Japan.
Free Radic Biol Med. 2021 Nov 20;176:356-365. doi: 10.1016/j.freeradbiomed.2021.10.008. Epub 2021 Oct 12.
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 α-tocopherol (α-Toc) but not by α-tocotrienol (α-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 α-Toc and α-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 α-Toc but not by α-Toc3. These results suggest that α-Toc and α-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 25-OHC induced the same type of cell death in each of the cell types examined, and that α-Toc and α-Toc3 exerted different effects, depending on the type of cell death.
24(S)-羟基胆固醇（24S-OHC）和 25-羟基胆固醇（25-OHC）分别由胆固醇 24-羟化酶和胆固醇 25-羟化酶产生。本研究的目的是确定这些氧化固醇在神经元细胞、肝细胞和角质形成细胞中诱导的细胞死亡类型，并阐明维生素 E 类似物对各种类型细胞死亡的抑制作用。在人神经元细胞（SH-SY5Y 细胞）中，24S-OHC 和 25-OHC 引起的细胞死亡不依赖于半胱天冬酶的激活。我们之前报道过，24S-OHC 通过酰基辅酶 A：胆固醇酰基转移酶 1（ACAT1）酯化和由此形成的类脂滴（LD）样结构是导致 24S-OHC 诱导的神经元细胞死亡的原因。在这里，我们发现 25-OHC 也诱导了神经元细胞中 ACAT1 介导的 25-OHC 酯化和 LD 形成。25-OHC 诱导的细胞死亡被 α-生育酚（α-Toc）抑制，但不被 α-生育三烯酚（α-Toc3）抑制，正如在 SH-SY5Y 细胞中 24S-OHC 诱导的细胞死亡一样。在人肝细胞（HepG2 细胞）中，这些氧化固醇引起一种不依赖于半胱天冬酶和氧化固醇酯化的细胞死亡。这种细胞死亡被 α-Toc 和 α-Toc3 抑制，表明在肝细胞中这些氧化固醇诱导的细胞死亡涉及自由基介导的脂质过氧化。在人角质形成细胞（HaCaT 细胞）中，这些氧化固醇引起一种依赖于半胱天冬酶但不依赖于氧化固醇酯化的细胞死亡，该死亡被 α-Toc 抑制，但不被 α-Toc3 抑制。这些结果表明，α-Toc 和 α-Toc3 以相同的方式作为自由基清除抗氧化剂，对抗氧化固醇诱导的细胞死亡，而在抑制神经元细胞和角质形成细胞的细胞死亡方面，它们的作用不同。总之，这些结果表明，24S-OHC 和 25-OHC 在每种被检测的细胞类型中诱导相同类型的细胞死亡，而 α-Toc 和 α-Toc3 则根据细胞死亡的类型产生不同的影响。
