Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA.
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA.
Cell Signal. 2012 Feb;24(2):484-492. doi: 10.1016/j.cellsig.2011.09.029. Epub 2011 Oct 1.
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.
流行病学研究表明，脂肪细胞因子瘦素与阿尔茨海默病（AD）的发病呈负相关，瘦素补充可减少淀粉样蛋白-β（Aβ）的产生和tau 磷酸化（p-tau），这两个主要的生化事件在 AD 的发病机制中起关键作用。我们之前已经表明，胆固醇氧化产物 27-羟胆固醇（27-OHC）抑制瘦素的表达，这种作用与 Aβ和 p-tau 水平的升高相关。我们还表明，27-OHC 诱导内质网（ER）应激，这是一种与 AD 相关的细胞反应，并赋予瘦素抵抗。然而，ER 应激在 27-OHC 诱导的瘦素表达下调中所起的作用尚未确定。在这项研究中，我们确定了 ER 应激在 27-OHC 诱导的 SH-SY5Y 人神经母细胞瘤细胞中瘦素表达下调中的作用。我们证明，27-OHC 诱导的 ER 应激通过激活 C/EBP 同源蛋白（CHOP）来减弱瘦素的表达，CHOP 负调控 C/EBPα，后者是瘦素表达所必需的转录因子。分子伴侣 4-苯基丁酸（4-PBA）可以防止 27-OHC 引起的 ER 应激和瘦素的下调。此外，我们证明了 CHOP 在 ER 应激下的激活在瘦素表达的下调中起着关键作用，因为敲低 CHOP 可减轻瘦素表达的下调。我们的研究表明，ER 应激是 27-OHC 诱导的瘦素负调控的机制联系，瘦素作为一种具有治疗 AD 潜力的激素，通过减少 Aβ和磷酸化 tau 的积累。
