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Cell Metabolism Jul 2013Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic...
Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.
Topics: Aged; Cholesterol Esters; Cohort Studies; Community Participation; Female; Genome, Human; Genome-Wide Association Study; Humans; Male; Massachusetts; Metabolome; Middle Aged; Transaminases; Triglycerides
PubMed: 23823483
DOI: 10.1016/j.cmet.2013.06.013 -
Current Opinion in Lipidology Dec 2023Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol... (Review)
Review
PURPOSE OF REVIEW
Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.
RECENT FINDINGS
In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1 -/- ), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC.
SUMMARY
Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.
Topics: Humans; Animals; Mice; Cholesterol, HDL; Cholesterol Esters; Cholesterol; Hypercholesterolemia; Atherosclerosis; Cholesterol Ester Transfer Proteins
PubMed: 37732779
DOI: 10.1097/MOL.0000000000000899 -
Biochimica Et Biophysica Acta Nov 2011Neutral lipids are a diverse family of hydrophobic biomolecules that have important roles in cellular biochemistry of all living species but have in common the property... (Review)
Review
Neutral lipids are a diverse family of hydrophobic biomolecules that have important roles in cellular biochemistry of all living species but have in common the property of charge neutrality. A large component of neutral lipids is the glycerolipids composed of triacylglycerols, diacylglycerols, and monoacylglycerols that can serve as cellular energy stores as well as signaling molecules. Another abundant lipid class in many cells is the cholesterol esters that are on one hand sterols and the other fatty acyl lipids, but in either case are neutral lipids involved in cholesterol homeostasis and transport in the blood. The analysis of these molecules in the context of lipidomics remains challenging because of their charge neutrality and the complex mixtures of molecular species present in cells. Various techniques have been used to ionize these neutral lipids prior to mass spectrometric analysis including electron ionization, atmospheric chemical ionization, electrospray ionization and matrix assisted laser desorption/ionization. Various approaches to deal with the complex mixture of molecular species have been developed including shotgun lipidomics and chromatographic-based separations such as gas chromatography, reversed phase liquid chromatography, and normal phase liquid chromatography. Several applications of these approaches are discussed. .
Topics: Analytic Sample Preparation Methods; Animals; Cholesterol Esters; Chromatography, Liquid; Glycerides; Humans; Lipid Metabolism; Mass Spectrometry
PubMed: 21757029
DOI: 10.1016/j.bbalip.2011.06.019 -
Cells Dec 20217-Ketocholesterol (7KCh) is a major oxidized cholesterol product abundant in lipoprotein deposits and atherosclerotic plaques. Our previous study has shown that 7KCh...
7-Ketocholesterol (7KCh) is a major oxidized cholesterol product abundant in lipoprotein deposits and atherosclerotic plaques. Our previous study has shown that 7KCh accumulates in erythrocytes of heart failure patients, and further investigation centered on how 7KCh may affect metabolism in cardiomyocytes. We applied metabolomics to study the metabolic changes in cardiac cell line HL-1 after treatment with 7KCh. Mevalonic acid (MVA) pathway-derived metabolites, such as farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate, phospholipids, and triacylglycerols levels significantly declined, while the levels of lysophospholipids, such as lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs), considerably increased in 7KCh-treated cells. Furthermore, the cholesterol content showed no significant change, but the production of cholesteryl esters was enhanced in the treated cells. To explore the possible mechanisms, we applied mRNA-sequencing (mRNA-seq) to study genes differentially expressed in 7KCh-treated cells. The transcriptomic analysis revealed that genes involved in lipid metabolic processes, including MVA biosynthesis and cholesterol transport and esterification, were differentially expressed in treated cells. Integrated analysis of both metabolomic and transcriptomic data suggests that 7KCh induces cholesteryl ester accumulation and reprogramming of lipid metabolism through altered transcription of such genes as sterol O-acyltransferase- and phospholipase A2-encoding genes. The 7KCh-induced reprogramming of lipid metabolism in cardiac cells may be implicated in the pathogenesis of cardiovascular diseases.
Topics: Animals; Cell Proliferation; Cholesterol Esters; Gene Expression Regulation; Intracellular Space; Ketocholesterols; Lipid Metabolism; Metabolome; Metabolomics; Mevalonic Acid; Mice; Models, Biological; Myocardium; RNA, Messenger; Transcription, Genetic; Triglycerides
PubMed: 34944104
DOI: 10.3390/cells10123597 -
Molecules (Basel, Switzerland) Dec 2022Due to the extensive use of agrochemicals resulting in the emergence of pesticide resistance and ecological environment problems, the research and development of new...
Due to the extensive use of agrochemicals resulting in the emergence of pesticide resistance and ecological environment problems, the research and development of new alternatives for crop protection is highly desirable. In order to discover potent natural product-based insecticide candidates, a series of new cholesterol ester derivatives containing cinnamic acid-like fragments at the C-7 position were synthesized. Some derivatives showed potent pesticidal activities. Against Walker, compounds , , , and showed 2.1-2.4-fold growth-inhibitory activity of the precursor cholesterol. Against Linnaeus, compounds , , and exhibited 1.9-2.1-fold insecticidal activity of cholesterol. These results will pave the way for the future synthesis of cholesterol-based derivatives as agrochemicals.
Topics: Animals; Pesticides; Cholesterol Esters; Molecular Structure; Moths; Insecticides; Structure-Activity Relationship
PubMed: 36500528
DOI: 10.3390/molecules27238437 -
Frontiers in Endocrinology 2020Esterification of cholesterol is a universal mechanism to store and transport large quantities of cholesterol between organs and tissues and to avoid toxicity of the... (Review)
Review
Esterification of cholesterol is a universal mechanism to store and transport large quantities of cholesterol between organs and tissues and to avoid toxicity of the excess of cellular cholesterol. Intended for transport and storage and thus to be inert, cholesteryl esters (CEs) reside in hydrophobic cores of circulating lipoproteins and intracellular lipid droplets. However, the inert identity of CEs is dramatically changed if cholesterol is esterified to a polyunsaturated fatty acid and subjected to oxidative modification. Post-synthetic, or epilipidomic, oxidative modifications of CEs are mediated by specialized enzymes, chief among them are lipoxygenases, and by free radical oxidation. The complex repertoire of oxidized CE (OxCE) products exhibit various, context-dependent biological activities, surveyed in this review. Oxidized fatty acyl chains in OxCE can be hydrolyzed and re-esterified, thus seeding oxidized moieties into phospholipids (PLs), with OxPLs having different from OxCEs biological activities. Technological advances in mass spectrometry and the development of new anti-OxCE antibodies make it possible to validate the presence and quantify the levels of OxCEs in human atherosclerotic lesions and plasma. The article discusses the prospects of measuring OxCE levels in plasma as a novel biomarker assay to evaluate risk of developing cardiovascular disease and efficacy of treatment.
Topics: Animals; Atherosclerosis; Cholesterol Esters; Humans; Oxidation-Reduction
PubMed: 33329402
DOI: 10.3389/fendo.2020.602252 -
Journal of Atherosclerosis and... 2011Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps... (Review)
Review
Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps in macrophage cholesterol trafficking. In the process of foam cell formation, excess free cholesterol undergoes esterification by acyl coenzyme A: acylcholesterol transferase 1 (ACAT-1), and fatty acid sterol esters are stored in cytoplasmic lipid droplets. The actions of ACAT-1 are opposed by neutral cholesterol ester hydrolase (nCEH), which generates free cholesterol and fatty acids. The resulting free cholesterol is a preferential source for cholesterol efflux into the extracellular space. Despite the important role of nCEH in protection against foam cell formation and atherosclerosis, the molecular identity of nCEH has long been debated. Although hormone-sensitive lipase (LIPE) has been proposed to be the nCEH in macrophages, recent evidence suggested the existence of other nCEH(s). We have recently identified a novel nCEH, neutral cholesterol ester hydrolase 1 (NCEH1), and demonstrated that NCEH1, in addition to LIPE, primarily mediates the hydrolysis of CE in macrophages. This review focuses on the protective roles of nCEHs in atherosclerosis, with special emphasis on the role of NCEH1.
Topics: Animals; Atherosclerosis; Cholesterol Esters; Foam Cells; Humans; Hydrolysis; Sterol Esterase
PubMed: 21467808
DOI: 10.5551/jat.7013 -
Redox Biology Feb 2019Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in...
Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD.
Topics: Aged; Animals; Biomarkers; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Chromatography, Liquid; Disease Models, Animal; Female; Hepatocytes; Humans; Lipid Metabolism; Liver X Receptors; Macrophages; Male; Mass Spectrometry; Metabolome; Mice; Middle Aged; Receptors, LDL
PubMed: 30576926
DOI: 10.1016/j.redox.2018.101069 -
Vascular Pharmacology 2010Accumulation of cholesteryl esters (CE) stored as cytoplasmic lipid droplets is the main characteristic of macrophage foam cells that are central to the development of... (Review)
Review
Accumulation of cholesteryl esters (CE) stored as cytoplasmic lipid droplets is the main characteristic of macrophage foam cells that are central to the development of atherosclerotic plaques. Since only unesterified or free cholesterol (FC) can be effluxed from the cells to extracellular cholesterol acceptors, hydrolysis of CE is the obligatory first step in CE mobilization from macrophages. This reaction, catalyzed by neutral cholesteryl ester hydrolase (CEH), is increasingly being recognized as the rate-limiting step in FC efflux. CEH, therefore, regulates the process of reverse cholesterol transport and ultimate elimination of cholesterol from the body. In this review, we summarize the earlier controversies surrounding the identity of CEH in macrophages, discuss the characteristics of the various candidates recognized to date and examine their role in mobilizing cellular CE and thus regulating atherogenesis. In addition, physiological requirements to hydrolyze lipid droplet-associated substrate and complexities of interfacial catalysis are also discussed to emphasize the importance of evaluating the biochemical characteristics of candidate enzymes that may be targeted in the future to attenuate atherosclerosis.
Topics: Animals; Atherosclerosis; Cholesterol Esters; Lipid Mobilization; Macrophages
PubMed: 19878739
DOI: 10.1016/j.vph.2009.10.002 -
Molecular Neurodegeneration Nov 2023This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment... (Review)
Review
This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated LDL-cholesterol (LDL-C) levels are well-established to cause cardiovascular disease and several LDL-C-lowering therapies are clinically available to manage this vascular risk factor. The efficacy of LDL-C-lowering therapies to reduce risk of all-cause dementia and AD is now important to address as recent studies demonstrate a role for LDL in Alzheimer's Disease (AD) as well as in all-cause dementia. The LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise LDL and lower HDL as CETP activity increases. Genetic and pharmacological studies support the hypothesis that CETP inhibition reduces cardiovascular risk by lowering LDL, which, by extension, may also lower VCID. Unlike humans, wild-type mice do not express catalytically active CETP and have HDL as their major lipoprotein fraction. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging LDL-lowering therapies for VCID will be discussed. Figure Legend. Cholesteryl Ester Transfer Protein in Alzheimer's Disease. CETP is mainly produced by the liver, and exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise circulating LDL and lower HDL as CETP activity increases. Low CETP activity is associated with better cardiovascular health, due to decreased LDL and increased HDL, which may also improve brain health. Although most peripheral lipoproteins cannot enter the brain parenchyma due to the BBB, it is increasingly appreciated that direct access to the vascular endothelium may enable peripheral lipoproteins to have indirect effects on brain health. Thus, lipoproteins may affect the cerebrovasculature from both sides of the BBB. Recent studies show an association between elevated plasma LDL, a well-known cardiovascular risk factor, and a higher risk of AD, and considerable evidence suggests that high HDL levels are associated with reduced CAA and lower neuroinflammation. Considering the potential detrimental role of LDL in AD and the importance of HDL's beneficial effects on endothelial cells, high CETP activity may lead to compromised BBB integrity, increased CAA deposits and greater neuroinflammation. Abbreviations: CETP - cholesteryl transfer ester protein; LDL - low-density lipoproteins; HDL - high-density lipoproteins; BBB - blood-brain barrier; CAA - cerebral amyloid angiopathy, SMC - smooth muscle cells, PVM - perivascular macrophages, RBC - red blood cells.
Topics: Humans; Mice; Animals; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, LDL; Alzheimer Disease; Endothelial Cells; Neuroinflammatory Diseases; Lipoproteins; Lipoproteins, HDL; Triglycerides
PubMed: 37974180
DOI: 10.1186/s13024-023-00671-y