The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors--relevance to Parkinson's disease.
The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors--relevance to Parkinson's disease.
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DOI：
10.1111/j.1471-4159.2011.07497.x
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发表时间：
2011-12
影响因子：
4.7
通讯作者：
Ghribi O
中科院分区：
文献类型：
--
作者：
Marwarha G;Rhen T;Schommer T;Ghribi O
多巴胺能神经元缺失和α-突触核蛋白积聚是帕金森病(PD)的两个主要病理特征。目前，控制多巴胺含量耗竭和α-突触核蛋白积累的机制尚不清楚。我们发现，在SH-SY5Y细胞中，氧固醇27-羟基胆固醇(27-OHC)降低了多巴胺合成中的限速酶酪氨酸羟基酶(TH)的表达，并增加了α-突触核蛋白的水平。然而，27-OHC作用的细胞机制尚未阐明。在这里，我们证明27-OHC通过雌激素受体(ER)和肝脏X受体(LXR)调节TH和α-突触核蛋白的表达水平。我们特别证明了ERβ的抑制介导了27-OHC诱导的TH表达的减少，这一作用被ER激动剂雌二醇逆转。我们还发现，27-OHC和LXR激动剂GW3965增加了α-突触核蛋白的表达，而LXR拮抗剂EchS显著减弱了27-OHC诱导的α-突触核蛋白表达的增加。我们进一步证明，LXRβ正向调节α-突触核蛋白的表达，27-OHC促进LXRβ介导的α-突触核蛋白转录。我们的结果表明，两条不同的途径参与了27-OHC对TH和α-突触核蛋白水平的调节。伴随着ERβ的激活和LXRβ的抑制，可以阻止27-OHC效应，因此可能通过阻止TH还原和α-突触核蛋白的积聚来减缓PD的进展。
Loss of dopaminergic neurons and α-synuclein accumulation are the two major pathological hallmarks of Parkinson’s disease (PD). Currently, the mechanisms governing depletion of dopamine content and α-synuclein accumulation are not well understood. We showed that the oxysterol 27-hydroxycholesterol (27-OHC) reduces the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and increases α-synuclein levels in SH-SY5Y cells. However, the cellular mechanisms involved in 27-OHC effects were not elucidated. Here, we demonstrate that 27-OHC regulates TH and α-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERβ mediates 27-OHC-induced decrease in TH expression, an effect reversed by the ER agonist estradiol. We also show that 27-OHC and the LXR agonist GW3965 increase α-synuclein while the LXR antagonist ECHS significantly attenuated the 27-OHC-induced increase in α-synuclein expression. We further demonstrate that LXRβ positively regulates α-synuclein expression and 27-OHC increases LXRβ-mediated α-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and α-synuclein levels. Concomitant activation of ERβ and inhibition of LXRβ prevent 27-OHC effects and may therefore reduce the progression of PD by precluding TH reduction and α-synuclein accumulation.
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影响因子：
14.8
作者：
Bosco, DA;Fowler, DM;Kelly, JW
通讯作者：
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