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lüll Endoplasmic reticulum stress-induced CHOP activation mediates the down-regulation of leptin in human neuroblastoma SH-SY5Y cells treated with the oxysterol 27-hydroxycholesterol Marwarha G; Dasari B; Ghribi OCell Signal 2012[Feb]; 24 (2): 484-492Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin and the onset of Alzheimer's disease (AD), and leptin supplementation decreases amyloid-beta (Abeta) 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 Abeta 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/EBPalpha, 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 Abeta and phosphorylated tau accumulation.|Alzheimer Disease/genetics/*metabolism/pathology[MESH]|Amyloid beta-Peptides/genetics/*metabolism[MESH]|Cell Line, Tumor[MESH]|Electrophoretic Mobility Shift Assay[MESH]|Endoplasmic Reticulum Stress[MESH]|Endoplasmic Reticulum/*drug effects/genetics/metabolism[MESH]|Gene Expression Regulation/drug effects[MESH]|Humans[MESH]|Hydroxycholesterols/*adverse effects[MESH]|Leptin/antagonists & inhibitors/genetics/*metabolism[MESH]|Neuroblastoma/genetics/*metabolism/pathology[MESH]|Phosphorylation[MESH]|RNA, Small Interfering/genetics/metabolism[MESH]|Real-Time Polymerase Chain Reaction[MESH]|Signal Transduction[MESH]|Transcription Factor CHOP/antagonists & inhibitors/genetics/*metabolism[MESH]|tau Proteins/genetics/*metabolism[MESH] |