High cholesterol level is essential for myelin membrane growth

Saher, Gesine; Brügger, Britta; Lappe-Siefke, Corinna; Möbius, Wiebke; Tozawa, Ryuichi; Wehr, Michael C.; Wieland, Felix; Ishibashi, Shun; Nave, Klaus‐Armin

doi:10.1038/nn1426

Cited by 639 publications

(613 citation statements)

References 44 publications

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“…LXRs are crucial for homeostasis of cholesterol (13), a major lipid constituent of myelin sheath, required for both oligodendrocyte maturation and myelination (14). The cerebellum is a CNS region known to be involved in motor coordination and spatial learning but also cognition and emotion (15).…”

Section: Discussionmentioning

confidence: 99%

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.

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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

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Section: Discussionmentioning

confidence: 99%

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.

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“…Inactivation of the squalene synthase gene (SQS/Fdft1) in VZ cells was obtained by crossing SQS flox/wt /nestin-Cre ϩ/Ϫ mice with SQS flox/flox mice (16,17). Embryos were genotyped by PCR.…”

Section: Methodsmentioning

confidence: 99%

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

Saito

Dubreuil

Arai

et al. 2009

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

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Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5-E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1-independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis.lipid droplets ͉ mass spectrometry ͉ neuroepithelial cells ͉ neurogenesis ͉ radial glia

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“…45,46 Myelin is composed of 70% cholesterol, and impaired cholesterol biosynthesis by disruption of the squalene synthase (an SREBP-controlled gene), has been shown to severely disrupt myelination. 47 The import of cholesterol in the central nervous system is restricted by the blood brain barrier, 10 hence de novo synthesis by glial cells is the major source of cholesterol in the brain. The transcription factors SREBP1 and SREBP2 are key players in the control of genes involved in the synthesis of cholesterol as well as fatty acids, phospholipids and triglycerides.…”

Section: Abnormalities In Myelination and Lipid Biosynthesis In Schizmentioning

confidence: 99%

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

et al. 2008

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Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 Â 10 À4 for SREBF1 (rs11868035, odd ration (OR) = 1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 Â 10 À5 for SREBF2 (rs1057217, OR = 1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.

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High cholesterol level is essential for myelin membrane growth

Cited by 639 publications

References 44 publications

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

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

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

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