Macrophage oxysterols and their binding proteins

Olkkonen, Vesa M.

doi:10.1097/mol.0b013e328356dba0

Cited by 27 publications

(29 citation statements)

References 112 publications

(80 reference statements)

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“…Together with our findings, both developments encourage the idea that 7KC could be efficiently A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 22 delivered in a combined therapy regiment in order to circumvent cancer MDR occurrence.…”

Section: Accepted Manuscriptsupporting

confidence: 76%

“…Cholesterol oxygenated derivatives termed oxysterols initially received great attention in the study of atherosclerosis, mainly due to its presence in human atherosclerotic tissue, however have been increasingly studied in relation to its anticancer potential [18][19][20]. Addition of a hydrophilic oxygenated functional group can be considered a catabolic pathway of cholesterol, reducing its half-life and targeting it either for removal or subsequent oxidations [21,22]. Some of the most physiologically important oxysterols are produced by mitochondrial hydroxylases of the cytochrome P450 superfamily (P450 CYP), e.g.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Rosa-Fernandes

Stern

Cavaglieri

et al. 2017

Journal of Proteomics

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Section: Accepted Manuscriptsupporting

confidence: 76%

Section: Accepted Manuscriptmentioning

confidence: 99%

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Rosa-Fernandes

Stern

Cavaglieri

et al. 2017

Journal of Proteomics

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“…25OHC binding to OSBPs may interfere with essential intracellular targeting and delivery of pathogen components (specific intracellular trafficking pathways will differ between pathogens). OSBPs have been implicated in both AD and ATH [330,331]; oxysterol binding to OSBPs in macrophages is thought to play a direct role in atheromatous plaque formation [332] and macrophage expression of OSBP2 (OSBP-L1) enhances ATH in susceptible mice [331]. The estrogen receptor ERα remains a further contender as a target for 25OHC [333].…”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

2014

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BackgroundAging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?DiscussionBoth ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.MechanismInfection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.SummaryWe postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

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“…In macrophages, 7-ketocholesterol, 7b-hydroxycholesterol, 5,6-epoxycholesterol and 25-hydroxycholesterol are implicated in the activation of apoptosis [5] and are believed to contribute to plaque formation. Atherosclerotic lesions are indeed enriched in 7b-hydroxycholesterol and 7-ketocholesterol, but also some products of enzymatic cholesterol oxidation such as 27-hydroxycholesterol, and 7a-and 25-hydroxycholesterol in lower concentrations and cholesterol 5,6-epoxides [6][7][8][9]. 27-hydroxylation of cholesterol is an important pathway for nuclear receptors LXR (Liver X Receptors) activation in response to cholesterol overload [10].…”

Section: Introductionmentioning

confidence: 99%

Bis(monoacylglycero)phosphate reduces oxysterol formation and apoptosis in macrophages exposed to oxidized LDL

Arnal-Levron

Chen

Delton-Vandenbroucke

et al. 2013

Biochemical Pharmacology

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Atherosclerosis is a major cardiovascular complication of diseases associated with increased oxidative stress that favors oxidation of circulating low density lipoproteins (LDLs). Oxidized LDL (oxLDL) is considered as highly atherogenic as it induces a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells and emergence of atherosclerotic plaque. OxLDL is enriched in oxidation products of cholesterol called oxysterols, some of which have been involved in the ability of oxLDL to induce cellular oxidative stress and cytotoxicity, mainly by apoptosis. Little is known about the possible contribution of cell-generated oxysterols toward LDL-associated oxysterols in cellular accumulation of oxysterols and related apoptosis. Using both radiochemical and mass analyzes, we showed that oxLDL greatly enhanced oxysterol production by RAW macrophages in comparison with unloaded cells or cells loaded with native LDL. Most oxysterols were produced by non-enzymatic routes (7-ketocholesterol and 7α/β-hydroyxycholesterol) but enzymatically formed 7α-, 25- and 27-hydroxycholesterol were also quantified. Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid preferentially found in late endosomes. We and others have highlighted the role of BMP in the regulation of intracellular cholesterol metabolism/traffic in macrophages. We here report that cellular BMP accumulation was associated with a significantly lower production of oxysterols upon oxLDL exposure. Of note, potent pro-apoptotic 7-ketocholesterol was the most markedly decreased. OxLDL-induced cell cytotoxicity and apoptosis were consistently attenuated in BMP-enriched cells. Taken together, our data suggest that BMP exerts a protective action against the pro-apoptotic effect of oxLDL via a reduced production of intracellular pro-apoptotic oxysterols.

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Macrophage oxysterols and their binding proteins

Cited by 27 publications

References 112 publications

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

Bis(monoacylglycero)phosphate reduces oxysterol formation and apoptosis in macrophages exposed to oxidized LDL

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