Liver X receptors regulate cholesterol homeostasis in oligodendrocytes

Nelissen, Katherine; Mulder, Monique; Smets, Ilse; Timmermans, Silke; Smeets, Karen; Ameloot, Marcel; Hendriks, Jerome J. A.

doi:10.1002/jnr.22743

Cited by 64 publications

(54 citation statements)

References 61 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We describe for the first time that Idol is involved in the regulation of lipid uptake in oligodendroglial cells. This finding is consistent with a recent report showing that liver X receptors (LXRs) that are transcriptional regulators of Idol expression control lipid metabolism in this cell type (Nelissen et al, 2012).…”

Section: Ndrg1 and Cmt4dsupporting

confidence: 93%

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Pietiäinen

Vassilev

Blom

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

Summary N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells.

show abstract

Section: Ndrg1 and Cmt4dsupporting

confidence: 93%

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Pietiäinen

Vassilev

Blom

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…We demonstrated both in vitro and ex vivo that LXR activation stimulates morphological cell maturation of oligodendroglial cells. Interestingly, Hendriks' group showed that a 72-h treatment with TO9 of late immature rat oligodendrocytes reduced cell branching (23). These data and ours suggest that LXR activation exerts a differential effect regarding the differentiation status of oligodendrocytes.…”

Section: Discussionsupporting

confidence: 77%

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Meffre

Shackleford

Hichor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.LXR alpha and beta | oligodendrocytes | cerebellum | myelination | oxysterols

show abstract

“…For instance, Apolipoproteins (APOD and APOE) were upregulated in both proximal and distal stumps of nerves treated with rapamycin + NGF, as well as in the distal stump of nerve treated only with NGF. These proteins increase axonal regeneration in PNS, and regulate oligodendrocyte differentiation and myelination in CNS, as well as protect neurons from apoptosis [102][103][104]. Serotransferrin (TF), which increases remyelination [105,106], was upregulated in both the proximal and distal stumps of nerves treated with rapamycin + NGF.…”

Section: Resultsmentioning

confidence: 99%

Autophagy in Peripheral Neuropathy

Osman¹

2017

Linköping University Medical Dissertations

View full text Add to dashboard Cite

Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor. Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy. In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury. Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits. 6 Populärvetenskaplig sammanfattningNervskador (neuropati) orsakade av sjukdomar eller olycksfall påverkar miljontals individer runt om i världen. Nervskador som orsakas av diabetes kallas diabetesneuropati och drabbar varannan patient med diabetes. Neuropati kan också orsakas av kronisk inflammation i nerven eller uppstå utan känd orsak, så kallad kronisk idiopatisk axonal polyneuropati. Patienterna som drabbas av neuropati uppvisar varierande symptom beroende på vilka nerver som drabbas men domningar, stickningar, smärta, känselbortfall och muskelsvaghet finns ofta i symptombilden. Nervskador efter trauma kräver oftast kirurgisk rekonstruktion. För närvarande finns det ingen behandling för diabetesneuropati. Allt fler människor i fysiskt aktiv ålder drabbas av åldersdiabetes (typ 2 diabetes). Detta leder till att fler patienter med diabetes drabbas av traumatiska nervskador som kräver nervreparation. Det är därför viktigt att utveckla reparationsmetoder som fungerar br...

show abstract

Liver X receptors regulate cholesterol homeostasis in oligodendrocytes

Cited by 64 publications

References 61 publications

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

Autophagy in Peripheral Neuropathy

Contact Info

Product

Resources

About