Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Department of Biosciences and Nutrition, Center for Biosciences, Novum, Sweden.
Mol Psychiatry. 2016 Jun;21(6):844-56. doi: 10.1038/mp.2015.133. Epub 2015 Sep 1.
Of the two isoforms of Liver X receptor (LXR), LXRβ has been shown to have major effects in the central nervous system (CNS) and on the regulation of aquaporins while LXRα has its most marked effects on cholesterol homeostasis. Both receptors have immunomodulatory functions. In LXRαβ knockout (ko) mice, the CNS phenotype is much more severe than in the LXRβ ko mice, suggesting a contribution of LXRα in CNS functions. One of the most striking abnormalities in the brains of LXRαβ ko mice is the occlusion of the lateral ventricles with age. In the present study, we have found by immunohistochemical staining that both LXRα and LXRβ are expressed in the cell nuclei of the epithelium of the choroid plexus and in the ependymal cells surrounding the lateral ventricles. The two receptors regulate several genes and can compensate for each other on expression of genes involved in structural integrity (E-cadherin, P-cadherin and β-catenin) and function (aquaporin 1 and carbonic anhydrase IX). Aquaporin 4 (AQ4) is not expressed in the choroid plexus but is expressed in the astrocytic end feet and ependymal cells. AQP4 expression was increased in white matter around lateral ventricles but not in neurons of LXRαβ ko mice. The data show that LXR is a regulator of cerebrospinal fluid (CSF) both at the choroid plexus and at the astrocytic end feet and defects in the synthesis of cerebrospinal fluid may be targeted by LXR agonists to facilitate CSF production, turnover and clearance in CNS diseases.
两种肝 X 受体（LXR）异构体中，LXRβ 已被证明在中枢神经系统（CNS）中具有重要作用，并对水通道蛋白的调节有影响，而 LXRα 对胆固醇稳态的影响最为显著。两种受体都具有免疫调节功能。在 LXRαβ 敲除（ko）小鼠中，CNS 表型比 LXRβ ko 小鼠更为严重，提示 LXRα 在 CNS 功能中起作用。LXRαβ ko 小鼠大脑中最显著的异常之一是随着年龄的增长侧脑室闭塞。在本研究中，我们通过免疫组织化学染色发现，LXRα 和 LXRβ 均表达于脉络丛上皮细胞的细胞核和侧脑室周围的室管膜细胞中。这两种受体调节多个基因，并可在参与结构完整性（E-钙黏蛋白、P-钙黏蛋白和β-连环蛋白）和功能（水通道蛋白 1 和碳酸酐酶 9）的基因表达上相互补偿。水通道蛋白 4（AQ4）不在脉络丛中表达，但在星形胶质细胞终足和室管膜细胞中表达。AQ4 在侧脑室周围白质中的表达增加，但在 LXRαβ ko 小鼠的神经元中不表达。数据表明，LXR 是脑脊液（CSF）的调节剂，既在脉络丛中起作用，也在星形胶质细胞终足中起作用，CSF 合成的缺陷可能是 LXR 激动剂的作用靶点，以促进 CNS 疾病中 CSF 的产生、周转和清除。
