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Review
. 2019 Aug 8;20(16):3858.
doi: 10.3390/ijms20163858.

Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?

Kevin Mouzat  1 , Aleksandra Chudinova  2 , Anne Polge  3 , Jovana Kantar  2 , William Camu  4 , Cédric Raoul  5 , Serge Lumbroso  2
Affiliations
Review

Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?

Kevin Mouzat et al. Int J Mol Sci. .

Abstract

Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.

Keywords: Alzheimer’s disease; Liver X receptors; amyotrophic lateral sclerosis; cholesterol; multiple sclerosis; neuroinflammation; oxysterols.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the LXR mode of action. (a) In their canonic mode of action, the RXR/LXR heterodimer is constitutively bound to DNA on its response elements (LXRE—whose consensus sequence is AGGTCAnnnnAGGTCA). In the absence of the ligand, the heterodimer interacts with co-repressors, maintaining the chromatin in a repressive transcriptional state. The binding of either an RXR or an LXR ligand (e.g., an oxysterol) induces conformational changes, which leads to the release of co-repressors and the recruitment of co-activators, and promotes a chromatin permissive transcriptional state and the activation of target genes. (b) In the trans-repression mechanism, binding of an LXR-ligand induces its SUMOylation. In macrophage, SUMOylated LXR stabilizes co-repressors on NF-κB, which, therefore, down-regulates the expression of the target gene. In astrocytes, SUMOylated LXR prevents target gene expression by blocking the binding of STAT1 to promoters. This trans-repression mechanism is a source of debate and its in vivo contribution to anti-inflammatory response still has to be confirmed. Green arrow: activation; red T bar: inhibition. LXR, Liver X Receptor. LXRE, LXR Responsive Element. RXR, Retinoid X Receptor. STAT1, signal transducer and activator of transcription 1. SUMO, small ubiquitin-like modifier.
Figure 2
Figure 2
Involvement of LXRs in neurodegenerative diseases. LXRs are central regulators of both cholesterol and oxysterol metabolisms. They have multiple roles in brain functions. Dysregulations of LXR-controlled metabolisms have been observed in neurodegenerative disorders. In amyotrophic lateral sclerosis, animal studies suggested that LXRs decrease neuroinflammation and act as neuroprotectors. Lxr-defective mice also have a motor phenotype mimicking ALS. In patients, cholesterol and oxysterol metabolism disturbances have been observed and LXR encoding-genes polymorphisms are associated with age at onset and survival time. In Alzheimer’s disease, treatment of AD animal models with an LXR agonist decreases neuroinflammation and reduces brain deposits. The cell culture and animal models also show that LXR could prevent synaptic defects. In patients, LXRα encoding-gene polymorphism is associated with a decrease in Tau and phospho-Tau levels in the CSF of patients, as well as in Aβ42 in the temporal cortex. APOE, whose allele ε4 is strongly associated with AD, is also an LXR-target gene. In multiple sclerosis, LXRs have been shown to promote myelination and remyelination and to decrease neuroinflammation. In patients, cholesterol and oxysterol metabolism have been observed and a missense genetic variant has been described as responsible for familial forms of primary progressive MS. LXR, Liver X Receptor. PPMS, Primary Progressive Multiple Sclerosis. RXR, Retinoid X Receptor.
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