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Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration.

ABSTRACT: Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXRγ. Silencing RXRγ in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXRγ. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.

SUBMITTER: Loera-Valencia R

PROVIDER: S-EPMC8639576 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism and antiviral defense.

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27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology.

Project description:The cholesterol metabolite and SERM, 27HC, is the signaling molecule that links cholesterol to breast cancer pathophysiology Hypercholesterolemia is a risk factor for breast cancer, and patients taking statins demonstrate lower breast cancer incidence and decreased breast cancer recurrence, data that highlights the potential importance of the recent finding that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, acts as a selective estrogen receptor modulator (SERM). The goal of this study was to evaluate the impact of 27HC on breast cancer pathophysiology. Elevation of 27HC in murine models increased tumor growth in an estrogen receptor dependent manner. Importantly, a high cholesterol diet decreased the time to tumor onset and increased tumor growth, and this response required presence of CYP27A1. Within human breast cancer samples, CYP27A1 expression increasesd with grade, in addition to being highly expressed in tumor associated macrophages. Finally 27HC increases metastasis to the lung. The findings herein strongly support a role for 27HC in breast cancer pathophysiology, providing support for the exploration of potential chemopreventative benefits of lower cholesterol diets, and pharmacological inhibitors of HMG-CoA reductase or CYP27A1. MCF-7 cells were treated as indicated in the presence of E2 or vehicle; RNA was isolated and used for preparation of label for 3' expression analysis.

2013-08-01 | E-GEOD-46924 | biostudies-arrayexpress

27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology

| S-ECPF-GEOD-46924 | biostudies-other

27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology.

2013-08-01 | GSE46924 | GEO

Connecting the Dots Between Hypercholesterolemia and Alzheimer's Disease: A Potential Mechanism Based on 27-Hydroxycholesterol.

Project description:Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects β-amyloid (Aβ) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.

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Project description:Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe(-/-) mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte-endothelial cell adhesion is increased by 27HC via estrogen receptor (ER)-dependent processes. In monocytes/macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ER?. In endothelial cells, 27HC is also proadhesive via ER?, and in contrast to estrogen, which blunts NF-?B activation, 27HC stimulates NF-?B activation via Erk1,2 and JNK-dependent I?B? degradation. Whereas 27HC administration to apoe(-/-) mice increases atherosclerosis, apoe(-/-);er?(-/-) are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ER?, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease.

| S-EPMC4098728 | biostudies-literature

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Project description:Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: A?42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as A?42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

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