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

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.

Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study

“…Moreover, when cholesterol was lowered, the Precursor Protein of Aβ (APP) was swallowed into cells to decompose, which could reduce the extracellular presence of Aβ and the risk of AD (Martins et al, 2009). Furthermore, oxysterols (oxidative metabolites of cholesterols) may participate in AD progression via Liver X Receptors (LXR), which are key components in cholesterol homeostasis (Gamba et al, 2019;Merino-Serrais et al, 2019;Mouzat et al, 2019). For example, 24-hydroxycholesterol (24-OHC) can impede hyperphosphorylation of tau induced by deposition of Aβ in SK-N-BE cells by regulating the deacetylase sirtuin 1.…”

LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis

“…CD4 + T cells provide essential protection against infection and cancer, but dysregulated T cell responses contribute to the pathogenesis of many diseases. LXRS are an attractive therapeutic target in many immunometabolic diseases involving T cells 33,34 . However, the actions of LXR in lymphocytes have not yet been fully investigated, particularly in human cells.…”

The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

“…Unlike cholesterol, oxysterols can cross the BBB from the brain to the circulation and vice versa, and the two main oxysterols are 24-hydroxycholesterol produced in the brain and 27-hydroxycholesterol primarily produced in the periphery [128,129]. Numerous studies have shown that oxysterols modulate the progression of AD through multiple pathways, including neuroinflammation, amyloid pathology, and neuronal death, which have been discussed in detail in comprehensive reviews [130][131][132][133].…”