scholarly journals 27-Hydroxycholesterol Promotes the Transfer of Astrocyte-Derived Cholesterol to Neurons in Co-cultured SH-SY5Y Cells and C6 Cells

2020 ◽  
Vol 8 ◽  
Author(s):  
Yushan Wang ◽  
Xiaona Zhang ◽  
Tao Wang ◽  
Wen Liu ◽  
Lijing Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cholesterol Metabolism ◽  
Feedback Mechanism ◽  
Cholesterol Homeostasis ◽  
Membrane Cholesterol ◽  
C6 Cells ◽  
Cholesterol Accumulation ◽  
Cholesterol Levels ◽  
Related Proteins ◽  
The Brain

Abnormality in cholesterol homeostasis in the brain is a feature of Alzheimer’s disease (AD). 27-Hydroxycholesterol (27-OHC) has been identified as a possible biomarker of AD, but its effects on cholesterol metabolism have not been fully characterized. This study was aimed to investigate the impacts of 27-OHC on cholesterol metabolism in nerve cells. SH-SY5Y cells and C6 cells were co-cultured and treated with 5, 10, and 20 μM 27-OHC for 24 h. Results showed that 27-OHC decreased cholesterol levels and up-regulated the expression of transport-related proteins in C6 cells. In SH-SY5Y cells, 27-OHC increased cholesterol accumulation, especially on plasma membrane (PM), which was consistent with the up-regulation of expressions of cholesterol endocytosis receptors, lipid raft-related proteins, and cholesterol esterase. Simultaneously, accumulation of membrane cholesterol promoted cholesterol conversion to 24S-OHC by CYP46A1(24S-hydroxylase) transfer from the endoplasmic reticulum (ER) to PM. Besides, Aβ levels were elevated in SH-SY5Y cells after 27-OHC treatment. Our results suggest that 27-OHC motivates the transfer of astrocyte-derived cholesterol to neurons. Although there exists a feedback mechanism that excessive cholesterol promotes its conversion to 24S-OHC, the increased cholesterol induced by 27-OHC could not be wholly offset in neurons.

scholarly journals 2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 562 ◽  
Author(s):  
Yiyang Zhao ◽  
Linkang He ◽  
Tian Wang ◽  
Lifang Zhu ◽  
Nianlong Yan
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Membrane Cholesterol ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway

Cholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activating ER stress in MDA-MB-231 cells. To further assess the detailed mechanisms between cholesterol metabolism, ER stress, and EMT, LXR-623 (an agonist of LXRα) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-β-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXRα expression and increasing Hydroxymethylglutaryl-Coenzyme A reductase (HMGCR) expression in MDA-MB-231 and BT-549 cells, which triggered ER stress and inhibited EMT. Meanwhile, tunicamycin-induced ER stress blocked the TGF-β/Smad signaling pathway. However, low HP-β-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-β receptor I levels in lipid rafts, which helped to activate TGF-β/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-β-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-β pathway-induced EMT. However, HP-β-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-β signaling pathways.

scholarly journals Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Claudia Villani ◽  
Giuseppina Sacchetti ◽  
Renzo Bagnati ◽  
Alice Passoni ◽  
Federica Fusco ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Potential Role ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Motor Deficits ◽  
Brain Cholesterol ◽  
Background Strain ◽  
Cholesterol Levels ◽  
The Brain

Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Oxysterols suppress constitutive fibrinogen expression

2003 ◽  
Vol 90 (07) ◽  
pp. 43-51 ◽  
Author(s):  
Hui Xia ◽  
Colvin Redman
Keyword(s):  
Apolipoprotein B ◽  
Hepg2 Cells ◽  
Cholesterol Metabolism ◽  
Acute Phase Protein ◽  
Feedback Mechanism ◽  
Cholesterol Homeostasis ◽  
Mrna Levels ◽  
Regulatory Pathway ◽  
Phase Protein ◽  
Artery Disease

SummaryElevated levels of both fibrinogen and cholesterol are risk factors in coronary artery disease. Previously we reported a metabolic link between fibrinogen and lipid metabolism in that HepG2 cells that were programmed by transfection of Bβ-fibrinogen cDNA to overexpress fibrinogen exhibited increased synthesis of cholesterol and increased secretion of apolipoprotein B. In this study we demonstrate that oxysterols, which participate in maintaining cholesterol homeostasis, also down regulate fibrinogen expression. Treatment of HepG2 cells with 25-hydroxycholesterol lowered fibrinogen Aα, Bβ and γ mRNA levels and inhibited fibrinogen synthesis and secretion but had no effect on α1-antitrypsin which, like fibrinogen, is an acute-phase protein. The inhibition of fibrinogen synthesis by oxysterols was maintained in interleukin-6 treated cells. Other oxysterols, that inhibit cholesterol synthesis by a feedback mechanism, also diminished fibrinogen expression in HepG2, rat H-4-II-E hepatoma cells and in primary human hepatocytes. Overexpression of SREBP-1 and SREBP-2 by transfection of HepG2 cells, or treatment with a synthetic LXRα agonist, which affect cholesterol metabolism, did not affect fibrinogen expression. We conclude that fibrinogen and cholesterol may share a novel common regulatory pathway.

scholarly journals Reprogramming cholesterol metabolism in macrophages and its role in host defense against cholesterol-dependent cytolysins

2022 ◽  
Author(s):  
Min-Sub Lee ◽  
Steven J. Bensinger
Keyword(s):  
Plasma Membrane ◽  
Host Defense ◽  
Mammalian Cells ◽  
Cholesterol Metabolism ◽  
Current Knowledge ◽  
Membrane Integrity ◽  
Cholesterol Homeostasis ◽  
Metabolic Reprogramming ◽  
Membrane Cholesterol ◽  
Plasma Membrane Cholesterol

AbstractCholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.

The role of diet during development on the regulation of adult cholesterol homeostasis

1985 ◽  
Vol 63 (5) ◽  
pp. 557-564 ◽  
Author(s):  
Sheila M. Innis
Keyword(s):  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Cholesterol Homeostasis ◽  
Cholesterol Levels ◽  
Effective Training ◽  
Cholesterol Intake ◽  
Lower Plasma Cholesterol ◽  
Altered Metabolism

Atherosclerosis is believed to begin early in life and to develop over several decades. Elevated plasma cholesterol is a major contributing factor. Studies in animals have shown that manipulation of cholesterol metabolism during its development in pre-and early post-natal life can permanently alter cholesterol synthesis and catabolism to favour lower plasma cholesterol levels in the adult faced with a high dietary cholesterol intake. Although the mechanisms and pathways involved are likely to be different, "metabolic training" can occur as a result of both the diet fed to the mother during gestation and lactation and from the diet fed to the animal itself in early life. The presence of cholesterol itself in the suckling diet does not appear to confer any lasting improvement to cholesterol handling in either man or animals. Although much research is still required to define the time in development for effective training of specific steps in cholesterol metabolism and the primary site and mechanism of permanently altered metabolism, significant progress has been made. These studies will form the basis of this review.

Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism

2008 ◽  
Vol 295 (6) ◽  
pp. E1341-E1348 ◽  
Author(s):  
E. M. E. van Straten ◽  
N. C. A. Huijkman ◽  
J. F. W. Baller ◽  
F. Kuipers ◽  
T. Plösch
Keyword(s):  
Fetal Development ◽  
Cholesterol Metabolism ◽  
In Utero ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Hepatic Expression ◽  
Cholesterol Levels

Cholesterol is critical for several cellular functions and essential for normal fetal development. Therefore, its metabolism is tightly controlled during all life stages. The liver X receptors-α (LXRα; NR1H3) and -β (LXRβ; NR1H2) are nuclear receptors that are of key relevance in coordinating cholesterol and fatty acid metabolism. The aim of this study was to elucidate whether fetal cholesterol metabolism can be influenced in utero via pharmacological activation of LXR and whether this would have long-term effects on cholesterol homeostasis. Administration of the LXR agonist T0901317 to pregnant mice via their diet (0.015% wt/wt) led to induced fetal hepatic expression levels of the cholesterol transporter genes Abcg5/g8 and Abca1, higher plasma cholesterol levels, and lower hepatic cholesterol levels compared with controls. These profound changes during fetal development did not affect cholesterol metabolism in adulthood nor did they influence coping with a high-fat/high-cholesterol diet. This study shows that the LXR system is functional in fetal mice and susceptible to pharmacological activation. Despite massive changes in fetal cholesterol metabolism, regulatory mechanisms involved in cholesterol metabolism return to a “normal” state in offspring and allow coping with a high-fat/high-cholesterol diet.

scholarly journals The Cholesteryl Ester Transfer Protein (CETP) raises Cholesterol Levels in the Brain and affects Presenilin-mediated Gene Regulation

2020 ◽  
Author(s):  
Felix Oestereich ◽  
Noosha Yousefpour ◽  
Ethan Yang ◽  
Alfredo Ribeiro-da-Silva ◽  
Pierre Chaurand ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Cholesterol Metabolism ◽  
High Cholesterol Diet ◽  
Transfer Protein ◽  
Brain Functions ◽  
Cholesterol Levels ◽  
Ldl Particles ◽  
The Impact ◽  
The Brain

AbstractThe cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very low levels of low-density lipoprotein (LDL) particles compared to humans. To understand how CETP activity affects the brain, we utilised CETP transgenic (CETPtg) mice showing elevated LDL levels on a high cholesterol diet inducing CETP expression. We found that CETPtg mice had up to 25% higher cholesterol levels in the brain. Using a microarray on astrocyte-derived mRNA, we found that this cholesterol increase is likely not due to astrocytic-dependent de novo synthesis of cholesterol. Rather, several genes linked to Alzheimer’s disease were altered in CETPtg mice. Most interestingly, we found activation of the G-protein coupled receptor EP4 and γ-secretase as upstream regulators of these transcriptional changes. Further in vitro studies showed that CETP expression was sufficient to activate γ-secretase activity. The data suggest that CETP activity affects brain’s health through modulating cholesterol levels and Alzheimer’s-related pathways. Therefore, CETPtg mice constitute a valuable research tool to investigate the impact of the cholesterol metabolism on brain functions.

Polyphenols can Potentially Prevent Atherosclerosis and Cardiovascular Disease by Modulating Macrophage Cholesterol Metabolism

2020 ◽  
Vol 14 (2) ◽  
pp. 175-190 ◽  
Author(s):  
Fumiaki Ito
Keyword(s):  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
Epidemiological Studies ◽  
Cholesterol Homeostasis ◽  
Cholesterol Accumulation ◽  
Cholesterol Uptake ◽  
Patients At Risk

Background: Arterial atherosclerosis is the main pathological cause of coronary artery disease and peripheral arterial disease. Atherosclerosis is a chronic condition characterized by the presence of cholesterol-rich macrophages in the arterial intima. Accumulation of cholesterol in these macrophages is due to increased oxidation of low-density lipoprotein (LDL) and its uptake via scavenger receptors on the macrophages. Cholesterol efflux from the cholesterol-laden macrophages into high-density lipoprotein (HDL) is also a key process in maintaining cholesterol homeostasis and prevention of cholesterol accumulation. Four pathways for the efflux of cholesterol to HDL exist in macrophages, including passive and active pathways. Several HDL characteristics determine cholesterol efflux capacity, namely composition, oxidative status, and HDL size. Oxidation of LDL and HDL as well as any imbalance in cholesterol uptake and efflux could lead to accumulation of cholesterol in macrophages and initiation of atherosclerogenesis. Conclusion: Epidemiological studies have demonstrated that polyphenol-rich foods reduce cardiovascular events in the general population and in patients at risk of cardiovascular diseases. Many studies have reported that polyphenols in polyphenol-rich foods have anti-atherosclerotic properties by preventing cholesterol accumulation in macrophages through the suppression of lipoproteins oxidation and regulation of cholesterol uptake and efflux.

scholarly journals miR-144 Mediates High Fat–Induced Changes of Cholesterol Metabolism via Direct Regulation of C/EBPα in the Liver and Isolated Hepatocytes of Yellow Catfish

2019 ◽  
Vol 150 (3) ◽  
pp. 464-474 ◽  
Author(s):  
Guanghui Chen ◽  
Kun Wu ◽  
Tao Zhao ◽  
Shicheng Ling ◽  
Wei Liu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Small Rna Sequencing ◽  
High Fat ◽  
Yellow Catfish ◽  
Cholesterol Accumulation ◽  
Induced Changes

ABSTRACT Background microRNAs (miRNAs) post-transcriptionally regulate gene expression and act as important modulators of cholesterol homeostasis. Objective The study explores the mechanism by which miRNAs mediate high fat–induced changes of cholesterol metabolism in yellow catfish. Methods Yellow catfish (weight: 3.79 ± 0.16 g, 3 mo old, mixed sex) were fed 2 diets containing lipids at 11.3% [control (CON)] or 15.4% [high-fat diet (HFD)] (by weight) for 8 wk. Cholesterol content was measured; hematoxylin-eosin (H&E) staining, qPCR assays, and small RNA sequencing were conducted in the liver. Hepatocytes were isolated from separate, untreated fish and incubated for 24 h in control solution or palmitic acid (PA; 0.25 mM)/oleic acid (OA; 0.5 mM) after 4 h pretreatment with or without miR-144 inhibitor/mimic (40 nM). Cholesterol content was measured; qPCR assays and Western blotting were conducted in the hepatocytes. HEK293T cells were co-transfected with plasmids to validate miR-144 target genes. The promoter activities of miR-144 were analyzed in HEK293T cells with PA (0.25 mM) or OA (0.25 or 0.5 mM) treatment for 24 h. Luciferase activity assays, electrophoretic mobility shift assay, and Western blotting were conducted in HEK293T cells. Results Compared with CON, HFD induced hepatic cholesterol accumulation (31.5%), and upregulated miR-144 expression (8.40-fold, P < 0.05). miR-144 directly targeted hydroxymethylglutaryl-CoA reductase (hmgcr), cholesterol 7α-monooxygenase A1 (cyp7a1), and adenosine triphosphate binding cassette transporter A1 (abca1) in HEK293T cells. In the hepatocytes of yellow catfish, miR-144 inversely regulated the expression of hmgcr, cyp7a1, and abca1 (30.3–78.5%, P < 0.05); loss of miR-144 function alleviated PA- or OA-induced cholesterol accumulation (19.5–61.1%, P < 0.05). We also characterized the C/EBPα binding site in the miR-144 promoter, and found that C/EBPα positively regulated miR-144 expression through binding to the miR-144 promoter. Conclusions miR-144 mediated HFD-induced changes in the liver and hepatocytes of yellow catfish, suggesting a possible mechanism for HFD-induced dysfunction in cholesterol metabolism.

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