Journal of Lipid Research (Nov 2016)

Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death[S]

  • Wakako Takabe,
  • Yasuomi Urano,
  • Diep-Khanh Ho Vo,
  • Kimiyuki Shibuya,
  • Masaki Tanno,
  • Hiroaki Kitagishi,
  • Toyoshi Fujimoto,
  • Noriko Noguchi

Journal volume & issue
Vol. 57, no. 11
pp. 2005 – 2014

Abstract

Read online

The 24(S)-hydroxycholesterol (24S-OHC), which plays an important role in maintaining brain cholesterol homeostasis, has been shown to possess neurotoxicity. We have previously reported that 24S-OHC esterification by ACAT1 and the resulting lipid droplet (LD) formation are responsible for 24S-OHC-induced cell death. In the present study, we investigate the functional roles of 24S-OHC esters and LD formation in 24S-OHC-induced cell death, and we identify four long-chain unsaturated fatty acids (oleic acid, linoleic acid, arachidonic acid, and DHA) with which 24S-OHC is esterified in human neuroblastoma SH-SY5Y cells treated with 24S-OHC. Here, we find that cotreatment of cells with 24S-OHC and each of these four unsaturated fatty acids increases prevalence of the corresponding 24S-OHC ester and exacerbates induction of cell death as compared with cell death induced by treatment with 24S-OHC alone. Using electron microscopy, we find in the present study that 24S-OHC induces formation of LD-like structures coupled with enlarged endoplasmic reticulum (ER) lumina, and that these effects are suppressed by treatment with ACAT inhibitor. Collectively, these results illustrate that ACAT1-catalyzed esterification of 24S-OHC with long-chain unsaturated fatty acid followed by formation of atypical LD-like structures at the ER membrane is a critical requirement for 24S-OHC-induced cell death.

Keywords