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

• Published in: International journal of molecular sciences 2019-08, Vol.20 (16), p.3858
• Main Authors: Mouzat, Kevin, Chudinova, Aleksandra, Polge, Anne, Kantar, Jovana, Camu, William, Raoul, Cédric, Lumbroso, Serge
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Animals; Axonal plasticity; Bile; Brain - metabolism; Cholesterol; Cholesterol - metabolism; CYP7A1 gene; Deoxyribonucleic acid; Disease Susceptibility; DNA; Epigenetics; Gene expression; Homeostasis; Humans; IL-1β; Inflammation; Interleukin 6; Life Sciences; Ligands; Lipid Metabolism; Lipids; Liver; Liver diseases; Liver X receptors; Liver X Receptors - chemistry; Liver X Receptors - metabolism; Metabolism; Myelin; Nervous system; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neuroprotection; Nitric oxide; Nitric-oxide synthase; Oxysterols - metabolism; Physiology; Review; Sheaths; Structure-Activity Relationship; Synaptogenesis; Transcription factors; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20163858

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.