Endoplasmic reticulum stress-induced CHOP activation mediates the down-regulation of leptin in human neuroblastoma SH-SY5Y cells treated with the oxysterol 27-hydroxycholesterol.
Endoplasmic reticulum stress-induced CHOP activation mediates the down-regulation of leptin in human neuroblastoma SH-SY5Y cells treated with the oxysterol 27-hydroxycholesterol.
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DOI：
10.1016/j.cellsig.2011.09.029
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发表时间：
2012-02
影响因子：
4.8
通讯作者：
Ghribi O
中科院分区：
文献类型：
--
作者：
Marwarha G;Dasari B;Ghribi O
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，补充瘦素可减少淀粉样蛋白-β (a β)的产生和tau蛋白磷酸化（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。我们之前已经证明，胆固醇氧化产物27-羟基胆固醇（27-OHC）抑制瘦素的表达，这种作用与Aβ和p-tau水平的增加有关。我们还发现27-羟色胺可诱导内质网（ER）应激，这是一种与AD相关的细胞反应，并导致瘦素抵抗。然而内质网应激在多大程度上参与27-羟色胺诱导的瘦素表达衰减尚未确定。在这项研究中，我们确定了内质网应激在27-羟色胺诱导的SH-SY5Y人神经母细胞瘤细胞瘦素表达衰减中的作用。我们证明27- ohc诱导的内质网应激通过激活C/EBP同源蛋白（CHOP）来减弱瘦素的表达，该蛋白负调控C/EBPα，这是瘦素表达所需的转录因子。分子伴侣4-苯基丁酸（4-PBA）阻止27-羟色胺引起的内质网应激和瘦素的下调。此外，我们证明转录因子CHOP在内质网应激下的激活是瘦素表达衰减的关键，因为敲低CHOP可以减轻瘦素表达的衰减。我们的研究提示内质网应激是27-羟色胺诱导瘦素负调控的机制环节，瘦素是一种通过减少a β和磷酸化tau积累对AD有潜在治疗作用的激素。
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.
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影响因子：
120.7
作者：
Lieb, Wolfgang;Beiser, Alexa S.;Vasan, Ramachandran S.;Tan, Zaldy S.;Au, Rhoda;Harris, Tamara B.;Roubenoff, Ronenn;Auerbach, Sanford;DeCarli, Charles;Wolf, Philip A.;Seshadri, Sudha
通讯作者：
Seshadri, Sudha
影响因子：
4.7
作者：
Marwarha G;Dasari B;Prabhakara JP;Schommer J;Ghribi O
通讯作者：
Ghribi O
影响因子：
2.5
作者：
Greco SJ;Sarkar S;Casadesus G;Zhu X;Smith MA;Ashford JW;Johnston JM;Tezapsidis N
通讯作者：
Tezapsidis N
影响因子：
1.7
作者：
Li, HY;Wang, LL;Yeh, RS
通讯作者：
Yeh, RS
DOI：
10.3233/jad-2010-1308
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Greco SJ;Bryan KJ;Sarkar S;Zhu X;Smith MA;Ashford JW;Johnston JM;Tezapsidis N;Casadesus G
通讯作者：
Casadesus G