Effect of vitamin E on 24(S)-hydroxycholesterol-induced necroptosis-like cell death and apoptosis

J Steroid Biochem Mol Biol. 2017 May;169:69-76. doi: 10.1016/j.jsbmb.2016.03.003. Epub 2016 Mar 4.

Abstract

24(S)-Hydroxycholesterol (24S-OHC) has diverse physiological and pathological functions. In particular, cytotoxic effects of 24S-OHC in neuronal cells are important in development of neurodegenerative diseases. 24S-OHC induces necroptosis-like cell death in SH-SY5Y cells expressing little caspase-8. In the present study, 24S-OHC was found to induce apoptosis as determined by caspase-3 activation in all-trans-retinoic acid (atRA)-treated SH-SY5Y cells in which expression of caspase-8 was induced. 24S-OHC-induced cell death was inhibited by α-tocopherol (α-Toc) but not by α-tocotrienol (α-Toc3) in SH-SY5Y cells regardless of whether cells were treated with atRA. In contrast, cumene hydroperoxide (CumOOH)-induced cell death was significantly inhibited by α-Toc and α-Toc3. In atRA-treated SH-SY5Y cells, generation of reactive oxygen species (ROS) was induced by stimulation with CumOOH but was not induced by stimulation with 24S-OHC. These results suggest that inhibition of 24S-OHC-induced cell death by α-Toc cannot be explained by its radical scavenging antioxidant activity. Esterification of 24S-OHC followed by lipid droplet (LD) formation due to acyl-CoA:cholesterol acyltransferase 1 (ACAT1) are key events in 24S-OHC-induced cell death in atRA-treated SH-SY5Y cells as demonstrated by inhibition of cell death by ACAT1 inhibitor. LD number was not changed by treatment with either α-Toc or α-Toc3. The different physical properties of α-Toc and α-Toc3 may account for their different inhibitory effects on 24S-OHC-induced cell death.

Keywords: 24(S)-hydroxycholesterol; Caspase-8; Cell death; Lipid droplet; α-Tocopherol; α-Tocotrienol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Apoptosis*
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Hydroxycholesterols / pharmacology*
  • Lipids / chemistry
  • Microscopy, Fluorescence
  • Neurons / drug effects*
  • Neurons / metabolism
  • Reactive Oxygen Species / metabolism
  • Tocotrienols / pharmacology
  • Tretinoin / pharmacology
  • Vitamin E / pharmacology*
  • alpha-Tocopherol / pharmacology

Substances

  • Antioxidants
  • Hydroxycholesterols
  • Lipids
  • Reactive Oxygen Species
  • Tocotrienols
  • Vitamin E
  • 24-hydroxycholesterol
  • Tretinoin
  • tocotrienol, alpha
  • alpha-Tocopherol