Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death

Abstract

Lipid peroxidation products have been known to induce cellular adaptive responses and enhance tolerance against subsequent oxidative stress through up-regulation of antioxidant compounds and enzymes. 24S-hydroxycholesterol (24SOHC) which is endogenously produced oxysterol in the brain plays an important role in maintaining brain cholesterol homeostasis. In this study, we evaluated adaptive responses induced by brain-specific oxysterol 24SOHC in human neuroblastoma SH-SY5Y cells. Cells treated with 24SOHC at sub-lethal concentrations showed significant reduction in cell death induced by subsequent treatment with 7-ketocholesterol (7KC) in both undifferentiated and retinoic acid-differentiated SH-SY5Y cells. These adaptive responses were also induced by other oxysterols such as 25-hydroxycholesterol and 27-hydroxycholesterol which are known to be ligands of liver X receptor (LXR). Co-treatment of 24SOHC with 9-cis retinoic acid, a retinoid X receptor ligand, enhanced the adaptive responses. Knockdown of LXRβ by siRNA diminished the adaptive responses induced by 24SOHC almost completely. The treatment with 24SOHC induced the expression of LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). The 24SOHC-induced adaptive responses were significantly attenuated by siRNA for ABCG1 but not by siRNA for ABCA1. Taken together, these results strongly suggest that 24SOHC at sub-lethal concentrations induces adaptive responses via transcriptional activation of LXR signaling pathway, thereby protecting neuronal cells from subsequent 7KC-induced cytotoxicity.

Effects of cholesterol oxides on cell death induction and calcium increase in human neuronal cells (SK-N-BE) and evaluation of the protective effects of docosahexaenoic acid (DHA; C22:6 n-3)

“…In both undifferentiated and retinoic acid differentiated SH-SY5Y cells, pretreatment with 24-OHC resulted in a significant reduction in cell death induced by subsequent treatment with 7KC [56]. Although its main role is to maintain brain cholesterol homeostasis, it was reported that 24S-OHC could induce cell death in various cell types, despite its ability to reduce Ab1-42 production and 7KC cytotoxicity [18].…”

New aspects of 24(S)-hydroxycholesterol in modulating neuronal cell death

“…When we treated undifferentiated SH-SY5Y cells with 24S-OHC, we observed that 24S-OHC exhibited cytotoxicity in a concentration-dependent manner (Fig. 1) [60,83,84]. 24S-OHC at concentrations higher than 10 M significantly caused cell death in which caspase-3 and caspase-9 were not activated [84].…”

“…Since the highly cytotoxic potential of 7-KC has been demonstrated in neuronal cells [57][58][59], 7-KC is suspected to be involved in the pathogenesis of neurodegenerative disease. In the case of 24S-OHC, stimulation of human neuroblastoma cell line (SH-SY5Y cells) with sublethal concentrations of 24S-OHC was found to induce adaptive response and protect the cells against subsequent cytotoxic stress induced by 7-KC [60]. The cytoprotective effect of 24S-OHC disappeared in LXR-knocked-down cells, suggesting that LXR played a key role in 24S-OHC-induced adaptive response.…”

“…LXR forms a functional heterodimer with retinoid X receptor (RXR) and regulates transcription of several genes involved in the cholesterol efflux pathway [61]. Co-treatment with 24S-OHC and 9-cis retinoic acid (the latter being a ligand of RXR) significantly enhanced adaptive response to prevent 7-KC-induced cell death [60]. Taken together, these results indicate that sublethal concentration of 24S-OHC protected neuronal cells against subsequent oxidative stress as a result of induction of an adaptive response in which the LXR/RXR was activated.…”

Accumulation of 24S-hydroxycholesterol in neuronal SK-N-BE cells treated with hexacosanoic acid (C26:0): Argument in favor of 24S-hydroxycholesterol as a potential biomarker of neurolipotoxicity

“…These complementary data obtained by flow cytometry and confocal microscopy suggest topographical modifications and clustering of CYP46A1 which could contribute to increase the activity of the enzyme, leading to higher 24S-OHC production. As 24S-OHC is a potent LXR agonist, which can counteract lipid induced cytotoxicity (especially 7KC-induced cell death of SH-SY-5Y neuronal cells via up-regulation of the ATP-binding cassette transporter A1 (ABCA1) [17], increased cellular level of 24S-OHC could occur as an adaptative response to neuronal damages. However, 24S-OHC can also increase amyloid toxicity in vitro by increasing oxidative stress [18].…”