Endoplasmic reticulum stress-induced CHOP activation mediates the down-regulation of leptin in human neuroblastoma SH-SY5Y cells treated with the oxysterol 27-hydroxycholesterol.

Abstract

Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin and the onset of Alzheimer's disease (AD), and leptin supplementation decreases amyloid-β (Aβ) production and tau phosphorylation (p-tau), two major biochemical events that play a key role in the pathogenesis of AD. We have previously shown that the cholesterol oxidized product 27-hydroxycholesterol (27-OHC) inhibits leptin expression, an effect that correlated with increased levels of Aβ and p-tau. We have also shown that 27-OHC induces endoplasmic reticulum (ER) stress, a cellular response that is implicated in AD and confers leptin resistance. However the extent to which ER stress is involved in 27-OHC-induced attenuation in leptin expression has not been determined. In this study we determined the involvement of ER stress in the 27-OHC-induced attenuation of leptin expression in SH-SY5Y human neuroblastoma cells. We demonstrate that 27-OHC-induced ER stress attenuates leptin expression by activating C/EBP Homologous Protein (CHOP) which negatively regulates C/EBPα, a transcription factor required for leptin expression. The molecular chaperone 4-phenylbutyric acid (4-PBA) precludes 27-OHC-evoked ER stress and down-regulation of leptin. Furthermore, we demonstrate that the activation of the transcription factor CHOP in response to ER stress is pivotal in the attenuation of leptin expression as knocking-down CHOP alleviates the attenuation in leptin expression. Our study implicates ER stress as the mechanistic link in the 27-OHC-induced negative regulation of leptin, a hormone that has potential therapeutic effects in AD by reducing Aβ and phosphorylated tau accumulation.

• Authors: Gurdeep Marwarha, Bhanu Dasari, Othman Ghribi
• Journal: Cellular signalling (Cell Signal) Vol. 24 Issue 2 Pg. 484-492 (Feb 2012) ISSN: 1873-3913 [Electronic] England
• PMID: 21983012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• DDIT3 protein, human
• Hydroxycholesterols
• Leptin
• RNA, Small Interfering
• tau Proteins
• Transcription Factor CHOP
• 27-hydroxycholesterol

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid beta-Peptides (genetics, metabolism)
• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Endoplasmic Reticulum (drug effects, genetics, metabolism)
• Endoplasmic Reticulum Stress
• Gene Expression Regulation (drug effects)
• Humans
• Hydroxycholesterols (adverse effects)
• Leptin (antagonists & inhibitors, genetics, metabolism)
• Neuroblastoma (genetics, metabolism, pathology)
• Phosphorylation
• RNA, Small Interfering (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Transcription Factor CHOP (antagonists & inhibitors, genetics, metabolism)
• tau Proteins (genetics, metabolism)