Liver X receptors regulate cerebrospinal fluid production

Abstract

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.