Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice

Berghoff, Stefan A.; Spieth, Lena; Sun, Ting; Hosang, Leon; Depp, Constanze; Sasmita, Andrew Octavian; Vasileva, M.; Scholz, Patricia; Zhao, Yang; Krueger‐Burg, Dilja; Wichert, Sven P.; Brown, Euan R.; Kyriakos, Michael; Nave, Klaus‐Armin; Bonn, Stefan; Odoardi, Francesca; Rossner, Moritz J.; Ischebeck, Till; Edgar, Julia M.; Saher, Gesine

doi:10.1101/2021.08.13.456070

Cited by 6 publications

(7 citation statements)

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“…For instance, LXR activation suppresses the expression of inflammatory genes by multiple mechanisms including cisrepression (Thomas et al, 2018), trans-repression (Ghisletti et al, 2007), and cholesterol efflux-mediated regulation (Yvan-Charvet et al, 2008;Ito et al, 2015). Similarly, LXR activation represses inflammatory genes and upregulates cholesterol efflux genes in myelin damage-associated microglia (Berghoff et al, 2021). In addition, macrophages have a favorable homeostatic role in atherosclerosis, helping to clear lipid debris derived from circulating lipoproteins and necrotic cells while tamping down inflammation (Endo-Umeda et al, 2022).…”

Section: Anti-atherosclerotic Effects Of Lxr Agonistsmentioning

confidence: 99%

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

Yang

Miao²,

Yu³

et al. 2023

Front. Mol. Biosci.

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Macrophages are involved in the whole process of atherosclerosis, which is characterized by accumulation of lipid and inflammation. Presently, clinically used lipid-lowering drugs cannot completely retard the progress of atherosclerosis. Liver X receptor (LXR) plays a key role in regulation of lipid metabolism and inflammation. Accumulating evidence have demonstrated that synthetic LXR agonists can significantly retard the development of atherosclerosis. However, these agonists induce sever hypertriglyceridemia and liver steatosis. These side effects have greatly limited their potential application for therapy of atherosclerosis. The rapid development of drug delivery system makes it possible to delivery interested drugs to special organs or cells using nanocarriers. Macrophages express various receptors which can recognize and ingest specially modified nanocarriers loaded with LXR agonists. In the past decades, a great progress has been made in this field. These macrophage-targeted nanocarriers loaded with LXR agonists are found to decrease atherosclerosis by reducing cholesterol accumulation and inflammatory reactions. Of important, these nanocarriers can alleviate side effects of LXR agonists. In this article, we briefly review the roles of macrophages in atherosclerosis, mechanisms of action of LXR agonists, and focus on the advances of macrophage-targeted nanocarriers loaded with LXR agonists. This work may promote the potential clinical application of these nanocarriers.

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Section: Anti-atherosclerotic Effects Of Lxr Agonistsmentioning

confidence: 99%

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

Yang

Miao²,

Yu³

et al. 2023

Front. Mol. Biosci.

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“…Along the same lines, DHCR24 inhibition and concomitant desmosterol accumulation, led to LXR-mediated synthesis of polyunsaturated fatty acids, which supported an anti-inflammatory and pro-resolving macrophage phenotype in a murine peritonitis model (Körner et al, 2019). Similarly, desmosterol-induced LXR activation in microglia contributed to inflammation resolution in multiple sclerosis (Berghoff et al, 2021). Interestingly, desmosterol accumulation was also observed in atherosclerotic foam cells, where it unexpectedly also suppressed inflammatory gene expression (Spann et al, 2012).…”

Section: Desmosterolmentioning

confidence: 86%

Cholesterol metabolism in the regulation of inflammatory responses

Bauer

Brüne²,

Schmid³

2023

Front. Pharmacol.

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The importance of biologically active lipid mediators, such as prostanoids, leukotrienes, and specialized pro-resolving mediators, in the regulation of inflammation is well established. While the relevance of cholesterol in the context of atherosclerosis is also widely accepted, the role of cholesterol and its biosynthetic precursors on inflammatory processes is less comprehensively described. In the present mini-review, we summarize the current understanding of the inflammation-regulatory properties of cholesterol and relevant biosynthetic intermediates taking into account the implications of different subcellular distributions. Finally, we discuss the inflammation-regulatory effect of cholesterol homeostasis in the context of SARS-CoV-2 infections.

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“…Another evidence of the involvement of cholesterol impairments in the pathogenesis of GC-induced brain lesion is that defects in brain cholesterol metabolism may be implicated in the pathology of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and some cognitive deficits typical of the old age. Neurons were also found to increase cholesterol synthesis in chronic myelin disease and multiple sclerosis (Berghoff et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Brain vitamin D3-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity

Lisakovska

Labudzynskyi

Khomenko

et al. 2023

Front. Cell. Neurosci.

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IntroductionVitamin D3 (VD3) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of glucocorticoid (GC) therapy. The aim of the study was to reveal the relationship between VD3 status and behavioral, structural-functional and molecular changes associated with GC-induced neurotoxicity.MethodsFemale Wistar rats received synthetic GC prednisolone (5 mg/kg b.w.) with or without VD3 (1000 IU/kg b.w.) for 30 days. Behavioral, histological, physiological, biochemical, molecular biological (RT-PCR, Western blotting) methods, and ELISA were used.Results and discussionThere was no difference in open field test (OFT), while forced swim test (FST) showed an increase in immobility time and a decrease in active behavior in prednisolone-treated rats, indicative of depressive changes. GC increased the perikaryon area, enlarged the size of the nuclei, and caused a slight reduction of cell density in CA1-CA3 hippocampal sections. We established a GC-induced decrease in the long-term potentiation (LTP) in CA1-CA3 hippocampal synapses, the amplitude of high K+-stimulated exocytosis, and the rate of Ca2+-dependent fusion of synaptic vesicles with synaptic plasma membranes. These changes were accompanied by an increase in nitration and poly(ADP)-ribosylation of cerebral proteins, suggesting the development of oxidative-nitrosative stress. Prednisolone upregulated the expression and phosphorylation of NF-κB p65 subunit at Ser311, whereas downregulating IκB. GC loading depleted the circulating pool of 25OHD3 in serum and CSF, elevated VDR mRNA and protein levels but had an inhibitory effect on CYP24A1 and VDBP expression. Vitamin D3 supplementation had an antidepressant-like effect, decreasing the immobility time and stimulating active behavior. VD3 caused a decrease in the size of the perikaryon and nucleus in CA1 hippocampal area. We found a recovery in depolarization-induced fusion of synaptic vesicles and long-term synaptic plasticity after VD3 treatment. VD3 diminished the intensity of oxidative-nitrosative stress, and suppressed the NF-κB activation. Its ameliorative effect on GC-induced neuroanatomical and behavioral abnormalities was accompanied by the 25OHD3 repletion and partial restoration of the VD3-auto/paracrine system.ConclusionGC-induced neurotoxicity and behavioral disturbances are associated with increased oxidative-nitrosative stress and impairments of VD3 metabolism. Thus, VD3 can be effective in preventing structural and functional abnormalities in the brain and behavior changes caused by long-term GC administration.

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Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice

Cited by 6 publications

References 53 publications

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

Cholesterol metabolism in the regulation of inflammatory responses

Brain vitamin D3-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity

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