Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve

Abstract

Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRα and β) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2-dependant antioxidant response. Interestingly, the reactive oxygen species scavenger N-acetylcysteine counteracts behavioral, electrophysical, ultrastructural and biochemical alterations in LXRdKO mice. Furthermore, Schwann cells in culture pretreated with LXR agonist, TO901317, exhibit improved defenses against oxidative stress generated by tert-butyl hydroperoxide, implying that LXRs play an important role in maintaining the redox homeostasis in the peripheral nervous system. Thus, LXR activation could be a promising strategy to protect from alteration of peripheral myelin resulting from a disturbance of redox homeostasis in Schwann cell.

Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells

“…On the other hand, most cells, including Schwann cells, have endogenous defense strategies to eliminate damages caused by excessive ROS production. Among them, the nuclear transcription factor erythroid-2-like factor 2 (Nrf2)/antioxidant response element (ARE) signaling is one of the critical antioxidant systems involved in the maintenance of the redox state for the defense of intracellular oxidative stress 13-15. One of the ARE-regulated phase II detoxifying enzymes regulated by Nrf2 is heme oxygenase-1 (HO-1), which catalyzes the degradation of heme to biliverdin, carbon oxide, and iron 16,17.…”

Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis

“…Since L-selectin is expressed on blood neutrophils and monocytes, we examined the impact of the absence of L-selectin on oxidative stress. Immunoblotting verified that MDA, a product of lipid peroxidation ( Liu et al, 2001 ) and marker for acute oxidative stress ( Esterbauer et al, 1991 ; Azbill et al, 1997 ; Hichor et al, 2018 ), was similarly present at very low levels in the uninjured spinal cords of mice of both genotypes ( p = 0.98; Fig. 2 ).…”

Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System

“…While the accumulation of lipid droplets in these mutant nerves comes as no surprise, the authors also show an increase in PMP22 protein levels coupled with improper processing of de novo PMP22 synthesis. Intriguingly, this is in stark contrast to what is observed in an LXR deficient system where the protein levels of PMP22 are downregulated [20,22]. Furthermore, both in primary Schwann cells and nerves, the authors demonstrate that ABCA1 and PMP22 proteins colocalize and can interact either directly or indirectly in a cholesterol dependent manner, without necessarily implicating LXRs.…”

“…The composition of myelin and the underlying biochemical and molecular mechanisms of myelination also contribute to a particular interest in studying Schwann cells. So far, the implication of LXRs and oxysterols in Schwann cell physiology has been studied using LXR null mice (LXα/β −/− hereafter referred to as LXR double KO or LXRdKO) [20,21,22].…”

“…This issue opened up the possibility of a secondary indirect mechanism in vivo that resulted in the reduced protein expression of these myelin genes. Upon further inspection, it was found that the systemic ablation of LXRs results in a highly oxidative environment in the sciatic nerve [22]. Indeed, despite a heightened response to oxidative stress through the Nrf2 pathway, anion superoxide production, protein carbonylation, and lipid peroxidation were elevated in the sciatic nerves of LXRdKO animals.…”