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

International audienceReactive 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. Liver X Receptors (LXRα and LXRβ) belong to the nuclear receptor superfamily of ligand-activated transcription factors. They regulate target gene expression by binding to specific responsive elements and are implicated in metabolic processes such as cholesterol turnover, inflammation as well as pathologies such as cancer and neu-rodegenerative diseases 1. Natural ligands of LXRs are oxysterols (i.e. 24(S)-hydroxycholesterol (24(S)-OH) or 25-hydroxycholesterol (25-OH)), produced either through auto-oxidation or enzymatic oxidation of cholesterol. Synthetic ligands of LXR, like TO901317, have also been discovered and are known to be potent activators of the LXR pathway. Previous studies have shown that mice where both LXR isoforms (LXRα and LXRβ) are deleted (LXR double KO or LXRdKO) exhibit altered lipid homeostasis in the brain resulting in neuronal loss, astrocytic proliferation , disorganized myelin sheaths and lipid accumulation in specific brain regions that participates in locomo-tor defects highlighted in these animals 2,3. We also observed that LXRdKO mice have thinner myelin sheaths surrounding axons of the sciatic nerve 4,5. Importantly, LXR inhibition enhanced myelin gene transcripts but decreased the amount of myelin proteins, suggesting post-translational modifications, detrimental for peripheral myelin integrity. Oxidative stress has been recently shown to alter the structure of myelin proteins in several diabetic peripheral neuropathies 6. In particular, PMP22 misfolding and aggregation provokes demyelination and nerve conduction velocity reduction. In line with this, our team recently showed that a burst of oxidative stress induced by Paraquat provokes a dramatic alteration of myelin structure in the sciatic nerves 7. Indeed, because of their high reactivity, reactive oxygen species (ROS) modify the structure and therefore the physiological functions of proteins and lipids. Thus, maintaining normal cellular ROS levels is essential. The excessive production of ROS or the decrease of antioxidant defenses is rather a hallmark characteristic in the pathogenesis of diseases such as diabetes, athero-sclerosis and neurodegeneration 8,9. Hence, compounds that exhibit anti-oxidative effects, triggering the intracel-lular cascade of protective pathways, may offer a promising strategy for therapeutic applications 10