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Journal of Alzheimer's Disease : JAD 2013Cholesterol metabolism is implicated in the etiology of Alzheimer's disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly... (Review)
Review
Cholesterol metabolism is implicated in the etiology of Alzheimer's disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly in vivo, the oxysterol, 24S-hydroxycholesterol (24-OHC), is the predominant metabolite of brain cholesterol and can be measured in the blood. The aim of this review is to evaluate plasma 24-OHC as a potential biomarker of AD risk and discuss factors related to its levels in the brain and blood. This systematic review examines studies published between 1950 and June 2012 that examined the relationship between plasma 24-OHC, cognition, brain structure, and dementia using the following key words ("24S-hydroxycholesterol" or "24-hydroxycholesterol") and ("Brain" or "Cognitive"). We found a total of 28 studies of plasma 24-OHC and neurodegenerative disease, including a subset of 12 that used dementia as a clinical endpoint. These studies vary in the direction of the observed associations. Results suggest plasma 24-OHC may be higher in the early stages of cognitive impairment and lower in more advanced stages of AD when compared to cognitively normal controls. Measures of 24-OHC in the blood may be an important potential marker for cholesterol metabolism in the brain and risk of AD. Further studies of plasma 24-OHC and dementia must account for the stage of disease, establish the temporal trends in oxysterol concentrations, and employ neuroimaging modalities to assess the structural and metabolic changes occurring in the brain prior to the onset of cognitive impairment.
Topics: Animals; Case-Control Studies; Cholesterol; Dementia; Humans; Hydroxycholesterols
PubMed: 23076077
DOI: 10.3233/JAD-2012-121585 -
Trends in Endocrinology and Metabolism:... Dec 2014Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in... (Review)
Review
Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in increased cholesterol content in cell membranes, thus impacting upon membrane fluidity and subsequent signaling. In addition, studies demonstrate that the metabolite, 27-hydroxycholesterol (27HC), can function as an estrogen, increasing the proliferation of estrogen receptor (ER)-positive breast cancer cells. This was unexpected because 27HC and other oxysterols activate the liver X receptors (LXR), resulting in a reduction of intracellular cholesterol. Resolution of this paradox will require dissection of the molecular mechanisms by which ER and LXR converge in breast cancer cells. Regardless, the observation that 27HC influences breast cancer provides a rationale for strategies that target cholesterol metabolism.
Topics: Breast Neoplasms; Cholesterol; Female; Humans; Hydroxycholesterols; Liver X Receptors; Orphan Nuclear Receptors; Receptors, Estrogen
PubMed: 25458418
DOI: 10.1016/j.tem.2014.10.001 -
Biochemical Pharmacology Feb 2022Direct translation of findings achieved in experimental cell or animal models to humans is quite a difficult task. We focused here only on the epidemiological and ex... (Review)
Review
Direct translation of findings achieved in experimental cell or animal models to humans is quite a difficult task. We focused here only on the epidemiological and ex vivo human studies so far available about the role of 27-hydroxycholesterol (27OHC) and related metabolism in cancer development. Some studies point to an adverse effect of 27OHC in breast cancer, based on the oxysterol's recognized ability to bind to and modulate estrogen receptors. The detrimental role of this side chain oxysterol would be evident in cancer progression, mainly in post-menopausal women and in an advanced stage of the disease. Other human researches, however, would rather correlate 27OHC intra-tumoral levels to a better prognosis. The analyses on human prostate cancer specimens performed to date are all against a detrimental contribution of 27OHC, rather suggesting interesting anti-prostate cancer effects exerted by this oxysterol. Finally, an increased 27OHC synthesis on the contrary seems to favour progression of late stage cancers in colon, brain and thyroid tissues, as found for breast cancer, possibly due to pro-inflammatory and pro-survival signalling triggered by disproportionate amounts of this oxysterol.
Topics: Animals; Biomarkers, Tumor; Cholestanetriol 26-Monooxygenase; Cytochrome P450 Family 7; Disease Progression; Humans; Hydroxycholesterols; Neoplasms; Steroid Hydroxylases
PubMed: 34023292
DOI: 10.1016/j.bcp.2021.114618 -
Trends in Endocrinology and Metabolism:... Apr 2011The cholesterol metabolite 27-hydroxycholesterol (27OHC) classically delivers sterols from peripheral tissues to the liver and is a substrate for bile acid synthesis.... (Review)
Review
The cholesterol metabolite 27-hydroxycholesterol (27OHC) classically delivers sterols from peripheral tissues to the liver and is a substrate for bile acid synthesis. Recent studies have revealed that 27OHC also binds to and modifies the function of estrogen receptors ERα and ERβ. Experiments in mice lacking the enzyme which synthesizes 27OHC, CYP27A1, or the enzyme which catabolizes 27OHC, CYP7B1, have demonstrated that 27OHC adversely affects estrogen-related cardiovascular protection and bone mineralization. Work in breast cancer cells further indicates that 27OHC alters ER target gene expression to promote cell growth. Therefore, 27OHC is the first identified endogenous selective estrogen receptor modulator (SERM) and could have an important impact upon the cardiovascular system, bone biology, and cancer.
Topics: Animals; Breast Neoplasms; Calcification, Physiologic; Cardiovascular System; Female; Humans; Hydroxycholesterols; Mice; Models, Biological; Selective Estrogen Receptor Modulators
PubMed: 21353593
DOI: 10.1016/j.tem.2011.01.003 -
Advanced Science (Weinheim,... Sep 2023Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid...
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients. The authors find that 7α, 25-OHC binding to its receptor Epstein-Barr virus-induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN-β, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN-γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2-deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane-induced SLE. Together, via sensing the oxysterol 7α, 25-OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.
Topics: Animals; Humans; Mice; Adaptive Immunity; Cytokines; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Hydroxycholesterols; Lupus Erythematosus, Systemic; Oxysterols; Receptors, G-Protein-Coupled
PubMed: 37469011
DOI: 10.1002/advs.202207108 -
Scientific Reports Jun 2023A growing body of evidence suggests that oxysterols such as 25-hydroxycholesterol (25HC) are biologically active and involved in many physiological and pathological...
A growing body of evidence suggests that oxysterols such as 25-hydroxycholesterol (25HC) are biologically active and involved in many physiological and pathological processes. Our previous study demonstrated that 25HC induces an innate immune response during viral infections by activating the integrin-focal adhesion kinase (FAK) pathway. 25HC produced the proinflammatory response by binding directly to integrins at a novel binding site (site II) and triggering the production of proinflammatory mediators such as tumor necrosis factor-α (TNF) and interleukin-6 (IL-6). 24-(S)-hydroxycholesterol (24HC), a structural isomer of 25HC, plays a critical role in cholesterol homeostasis in the human brain and is implicated in multiple inflammatory conditions, including Alzheimer's disease. However, whether 24HC can induce a proinflammatory response like 25HC in non-neuronal cells has not been studied and remains unknown. The aim of this study was to examine whether 24HC produces such an immune response using in silico and in vitro experiments. Our results indicate that despite being a structural isomer of 25HC, 24HC binds at site II in a distinct binding mode, engages in varied residue interactions, and produces significant conformational changes in the specificity-determining loop (SDL). In addition, our surface plasmon resonance (SPR) study reveals that 24HC could directly bind to integrin αvβ3, with a binding affinity three-fold lower than 25HC. Furthermore, our in vitro studies with macrophages support the involvement of FAK and NFκB signaling pathways in triggering 24HC-mediated production of TNF. Thus, we have identified 24HC as another oxysterol that binds to integrin αvβ3 and promotes a proinflammatory response via the integrin-FAK-NFκB pathway.
Topics: Computer Simulation; Humans; Integrin alphaVbeta3; Hydroxycholesterols; Inflammation; Signal Transduction; Macrophages; Models, Molecular; Thermodynamics; Protein Conformation; Surface Plasmon Resonance; Cholesterol 24-Hydroxylase
PubMed: 37280310
DOI: 10.1038/s41598-023-36040-4 -
Current Aging Science 2020There is a huge demand for efficient strategies for maintaining cognitive wellbeing with age, especially in the context of population aging. Dementia constitutes the... (Review)
Review
BACKGROUND
There is a huge demand for efficient strategies for maintaining cognitive wellbeing with age, especially in the context of population aging. Dementia constitutes the main reason for disability and dependency in the elderly. Identification of potential risk and protective factors, as well as determinants of conversion from MCI to dementia, is therefore crucial. In case of Alzheimer's disease, the most prevalent dementia syndrome amongst the members of modern societies, neurodegenerative processes in the brain can begin many years before first clinical symptoms appear. First functional changes typically mean advanced neuron loss, therefore, the earliest possible diagnosis is critical for implementation of promising early pharmaceutical interventions.
OBJECTIVE
The study aimed to discuss the relationships between both circulating and brain cholesterol with cognition, and explore its potential role in early diagnosis of cognitive disorders.
METHODS
Literature review.
RESULTS
The causal role of high cholesterol levels in AD or MCI has not been confirmed. It has been postulated that plasma levels of 24(S)-OHC can potentially be used as an early biochemical marker of altered cholesterol homeostasis in the CNS. Some studies brought conflicting results, finding normal or lowered levels of 24(S)-OHC in dementia patients compared to controls. In spite of decades of research on the relationship between cholesterol and dementia, so far, no single trusted indicator of an early cognitive deterioration has been identified.
CONCLUSION
The current state of knowledge makes the use of cholesterol markers of cognitive decline in clinical practice impossible.
Topics: Animals; Brain; Cholesterol; Cognition; Dementia; Humans; Hydroxycholesterols
PubMed: 31530269
DOI: 10.2174/1874609812666190917155400 -
American Journal of Respiratory Cell... Dec 2023
Topics: Mice; Animals; SARS-CoV-2; COVID-19; Hydroxycholesterols; Biology
PubMed: 37672661
DOI: 10.1165/rcmb.2023-0301ED -
The Journal of Steroid Biochemistry and... Nov 2023The oxysterol 27-hydroxycholesterol (27OHC) is produced by the enzyme sterol 27-hydroxylase (Cyp27A1) and is mainly catabolized to 7α-Hydroxy-3-oxo-4-cholestenoic acid...
The oxysterol 27-hydroxycholesterol (27OHC) is produced by the enzyme sterol 27-hydroxylase (Cyp27A1) and is mainly catabolized to 7α-Hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) by the enzyme cytochrome P-450 oxysterol 7α-hydroxylase (Cyp7B1). 27OHC is mostly produced in the liver and can reach the brain by crossing the blood-brain barrier. A large body of evidence shows that CYP27A1 overexpression and high levels of 27OHC have a detrimental effect on the brain, causing cognitive and synaptic dysfunction together with a decrease in glucose uptake in mice. In this work, we analyzed two mouse models with high levels of 27OHC: Cyp7B1 knock-out mice and CYP27A1 overexpressing mice. Despite the accumulation of 27OHC in both models, Cyp7B1 knock-out mice maintained intact learning and memory capacities, neuronal morphology, and brain glucose uptake over time. Neurons treated with the Cyp7B1 metabolite 7-HOCA did not show changes in synaptic genes and 27OHC-treated Cyp7B1 knock-out neurons could not counteract 27OHC detrimental effects. This suggests that 7-HOCA and Cyp7B1 deletion in neurons do not mediate the neuroprotective effects observed in Cyp7B1 knock-out animals. RNA-seq of neuronal nuclei sorted from Cyp7B1 knock-out brains revealed upregulation of genes likely to confer neuroprotection to these animals. Differently from Cyp7B1 knock-out mice, transcriptomic data from CYP27A1 overexpressing neurons showed significant downregulation of genes associated with synaptic function and several metabolic processes. Our results suggest that the differences observed in the two models may be mediated by the higher levels of Cyp7B1 substrates such as 25-hydroxycholesterol and 3β-Adiol in the knock-out mice and that CYP27A1 overexpressing mice may be a more suitable model for studying 27-OHC-specific signaling. We believe that future studies on Cyp7B1 and Cyp27A1 will contribute to a better understanding of the pathogenic mechanisms of neurodegenerative diseases like Alzheimer's disease and may lead to potential new therapeutic approaches.
Topics: Animals; Mice; Steroid Hydroxylases; Cytochrome P-450 Enzyme System; Hydroxycholesterols; Oxysterols; Cognition; Disease Models, Animal; Mice, Knockout; Glucose
PubMed: 37648096
DOI: 10.1016/j.jsbmb.2023.106387 -
Oncogene May 2022Dietary cholesterol has been implicated to promote lung cancer. Lung adenocarcinoma (LAC) is a main type of lung cancer, whereas the functional mechanism of cholesterol...
Dietary cholesterol has been implicated to promote lung cancer. Lung adenocarcinoma (LAC) is a main type of lung cancer, whereas the functional mechanism of cholesterol in LAC remained largely unknown. In the present study, we evidenced that cholesterol promoted cell proliferation and invasion of LAC in vitro as well as LAC metastasis in vivo. Cyp27A1 knockdown reduced the cholesterol-induced LAC cells proliferation and invasion. In contrast, Cyp7B1 knockdown enhanced the effect of cholesterol on LAC cells proliferation and invasion. Furthermore, Cyp27A1 deficiency remarkably reduced high cholesterol-induced LAC metastasis in vivo. Mechanism investigation demonstrated that exposure of LAC cells to 27-hydroxycholesterol induced the phosphorylation of AKT and NFκB p65, and promoted the expression of peptidylprolyl isomerase B (PPIB), especially in the coculture with THP1-derived macrophage. Meanwhile, 27-hydroxycholesterol induced the secretion of FGF2 and IL-6, which contributed to the expression of snail and vimentin. Luciferase report assay and ChIP assay confirmed that NFκB p65 controlled the transcription of PPIB. Inhibiting NFκB p65 activation reduced PPIB expression. PPIB inhibition reduced 27-hydroxycholesterol-induced expression of snail and vimentin. These results indicated that 27-hydroxycholesterol linked high cholesterol and LAC metastasis by regulating NFκB/PPIB axis and the secretion of FGF2 and IL-6.
Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Cell Proliferation; Diet; Fibroblast Growth Factor 2; Humans; Hydroxycholesterols; Interleukin-6; Lung Neoplasms; Neoplasm Invasiveness; Vimentin
PubMed: 35379924
DOI: 10.1038/s41388-022-02285-y