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.
Highlights
Liver X Receptors (LXRs) are lipid-activated transcription factors that belong to the nuclear receptor superfamily [1]
Since cholesterol and oxysterol homeostasis are crucial to a correct development and maintenance of central nervous system (CNS) functions, and LXRs are central regulators of their metabolism, it is tempting to suggest that dysregulations of LXRs could be involved in the risk of developing neurological diseases, and/or in the modulation of their natural history
Cholesterol and oxysterol metabolism has demonstrated their pivotal role in maintaining brain homeostasis
Summary
Liver X Receptors (LXRs) are lipid-activated transcription factors that belong to the nuclear receptor superfamily [1]. Since their identification in the mid-1990s [2,3], they have been the focus of many studies. The growing interest for LXRs and the generation of mice with genetic ablation of Lxrs [5] has shed light on their pivotal role in many physiological functions, including endocrine system [6], female and male fertility [7,8], inflammation, and immune processes [9] Pathological conditions, such as cancer, have been studied [10]. LXR roles in the nervous system have been widely reported, and these nuclear receptors could be involved in neurodegenerative disorders [11]
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