Neuronal LXR Regulates Neuregulin 1 Expression and Sciatic Nerve-Associated Cell Signaling in Western Diet-fed Rodents

Abstract

Neuropathic pain caused by peripheral nerve injuries significantly affects sensory perception and quality of life. Accumulating evidence strongly link cholesterol with development and progression of Obesity and Diabetes associated-neuropathies. However, the exact mechanisms of how cholesterol/ lipid metabolism in peripheral nervous system (PNS) contributes to the pathogenesis of neuropathy remains poorly understood. Dysregulation of LXR pathways have been identified in many neuropathic models. The cholesterol sensor, LXR α/β, expressed in sensory neurons are necessary for proper peripheral nerve function. Deletion of LXR α/β from sensory neurons lead to pain-like behaviors. In this study, we identified that LXR α/β expressed in sensory neurons regulates neuronal Neuregulin 1 (Nrg1), protein involved in cell-cell communication. Using in vivo cell-specific approaches, we observed that loss of LXR from sensory neurons altered genes in non-neuronal cells located in the sciatic nerve (potentially representing Schwann cells (SC)). Our data suggest that neuronal LXRs may regulate non-neuronal cell function via a Nrg1-dependent mechanism. The decrease in Nrg1 expression in DRG neurons of WD-fed mice may suggest an altered Nrg1-dependent neuron-SC communication in Obesity. The communication between neurons and non-neuronal cells such as SC could be a new biological pathway to study and understand the molecular and cellular mechanism underlying Obesity-associated neuropathy and PNS dysfunction. Peripheral neuropathy arising from metabolic disorders such as Obesity and pre-diabetes leads to loss of sensory perception, pain, and reduced quality of life 1-3. Currently, there are no disease modifying drugs available, as the neurobiology underlying this type ofneuropathic pain is still unclear. Many previous studies have focused on glucose as a major culprit in the development of diabetes-associated neuropathies 4-6 , but recent body of evidence indicated that altered lipid signaling in the peripheral nervous system (PNS) 7-10 is involved. Evidence in obese and diabetic patients, in addition to murine model of type II diabetes and pre-diabetes strongly suggest that circulating cholesterol and cholesterol pathways are linked to development and progression of neuropathy 11-13. Notably, sensory neurons located in the dorsal root ganglia (DRG) and associated Schwann cells (SC), satellite cells or immune cells in the nerves are not protected from the blood-brain or blood-nerve barrier 14 suggesting that, in contrast to the central nervous system (CNS), they could sense and/or be affected by circulating lipids. Previously, we found that peripheral neurons express cholesterol sensor and transcription factor: liver X receptors (LXR α/β) (NR1H3 and NR1H2) 15-17. LXR α/β are ligand-activated nuclear receptors that bind metabolites of cholesterol 18,19. Many previous findings strongly suggested that, LXRs play an important role in nervous systems 16,17 but, while the function of LXR α/β in regulating cholesterol efflux (in liver, intestin...

LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice

“…This improvement in pain indices was also accompanied with an increase in SBNP density suggesting LXRs activation either attenuated distal degeneration or stimulated nerve regeneration. This is consistent with our prior studies that showed LXR agonist treatment prevents progression of obesity-induced allodynia by altering peripheral sensory neuron function and their interaction with associated cells [ 10 , 62 ]. Peripheral macrophages have been implicated in the development of mechanical allodynia [ 63 ] and infiltration by immune cells happen differently in myelinated or non-myelinated fibers that may explain temporal differences in sensory behavior.…”

“…LXRs are oxidized cholesterol derivative ligand-activated transcription factors and consist of two isoforms LXRα and LXRβ [ 10 , 30 , 31 , 62 ]. LXRs play an important role in cholesterol metabolism [ 32 , 33 ].…”

LXR agonist Prevents Peripheral Neuropathy and modifies PNS immune cells in Aged Mice

“…We therefore tested the hypothesis that activation of LXRs can be effective in delaying/improving the progression of and found that the LXR selective agonist GW3965 either reversed or delayed the progression of multiple indices of neuropathy. This is consistent with our prior studies that showed LXR agonist treatment prevents progression of obesity-induced allodynia by altering peripheral sensory neuron function and their interaction with associated cells [9, 43]. Our findings suggest that activation of LXRs may influence sensory perception of the aged mice via activation of LXRs in macrophages of the SN that induces the M2 phenotype involved in nerve regeneration.…”

“…LXRs are oxidized cholesterol derivative ligand-activated transcription factors and consist of two isoforms LXRα and LXRß [9, 24, 25, 43]. LXRs play an important role in cholesterol metabolism [26, 27].…”

The Pathological Links between Adiposity and the Carpal Tunnel Syndrome

“…Gavini et al showed that the LXR reduces the proliferation of the Schwann cells in obesity. The effect was directly related to the downregulation of neurogenin 1 by saturated fatty acids [ 80 ]. The same group found also that activation of LXR can reduce pain in diet-induced obesity.…”