LXR Regulation of Brain Cholesterol: From Development to Disease

Abstract

Liver X Receptors (LXRs) are master regulators of cholesterol homeostasis and inflammation in the central nervous system (CNS). The brain, which contains a disproportionately large amount of the body's total cholesterol (~25%), requires a complex and delicately balanced cholesterol metabolism to maintain neuronal function. Dysregulation of cholesterol metabolism has been implicated in a number of neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases, among others. Due to their cholesterol sensing and anti-inflammatory activities, LXRs are positioned centrally in the everyday maintenance of central nervous system function. This review will focus on recent research into the role of LXRs in the CNS during normal development and homeostasis and in disease states.

Transcriptional control of microglia phenotypes in health and disease

“…LXRs and RXRs. Liver X receptors (LXRs) and retinoid X receptors (RXRs) are nonsteroid nuclear receptors that play key roles in cholesterol homeostasis and inflammation (118,119). The LXR isoforms LXRα and LXRβ can form dimers with any of the three RXR isoforms (RXRα, RXRβ, and RXRγ) and are activated in the presence of cholesterol derivatives such as oxysterols.…”

“…LXRs have antiinflammatory effects and modify macrophage phagocytic capability (120). Age-related neurodegenerative conditions have been linked to the disruption of cholesterol metabolism and LXR signaling (118). Likewise, LXR agonists have been shown to produce cognitive improvement in AD mouse models (121)(122)(123), but the mechanisms are not well understood.…”

Idolizing the clearance of Amyloid-β by microglia

“…ApoE is a component of lipoproteins such as very low density lipoprotein and high density lipoprotein and has been implicated in cholesterol transport. Its transcription is regulated by liver X receptor (LXR) transcription factors in a tissue-dependent manner (3). Several ApoE isoforms exist, and it is now established that the ApoE2 allele is associated with a reduced AD risk, while carriers of the ApoE4 allele are at an increased risk to develop AD.…”

“…LXRs play an important role in maintenance of sterol homeostasis in the CNS (3), and loss of either LXRα or LXRβ exacerbates AD-like pathology in an Aβ amyloidosis mouse model (11). Conversely, pharmacological activation of LXRs has been shown to decrease amyloidosis, reduce neuroinflammation and improve cognitive function in mouse models of AD (3,6,12,13). The beneficial outcome of LXR activation in AD has been attributed to (I) repression of proinflammatory signaling; (II) increased expression of ApoE and ABCA1 and (III) increased lipidation of ApoE by ABCA1, which supports enhanced Aβ clearance (Figure 1).…”

Clinical and laboratory features of ALS

“…LXR/RXR and FXR/RXR are nuclear receptors. This canonical pathway is related to lipid metabolism and inflammation in the central nervous system [306,307] . These have been previously implicated in ALS.…”