Review

Authors: Baiba K Gillard, Corina Rosales, Antonio M Gotto...

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

Review

Authors: Robert C Murphy, Thomas J Leiker, Robert M Barkley...

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

Review

Authors: Tetiana Poliakova, Cheryl L Wellington

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

Authors: Shuyuan Guo, Jianhong Lu, Yujuan Zhuo...

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

Authors: Mei-Ling Cheng, Hsiang-Yu Tang, Pei-Ting Wu...

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

Authors: Jolanda M P Liefhebber, Charlotte V Hague, Qifeng Zhang...

In hepatitis C virus infection, replication of the viral genome and virion assembly are linked to cellular metabolic processes. In particular, lipid droplets, which store principally triacylglycerides (TAGs) and cholesterol esters (CEs), have been implicated in production of infectious virus. Here, we examine the effect on productive infection of triacsin C and YIC-C8-434, which inhibit synthesis of TAGs and CEs by targeting long-chain acyl-CoA synthetase and acyl-CoA:cholesterol acyltransferase, respectively. Our results present high resolution data on the acylglycerol and cholesterol ester species that were affected by the compounds. Moreover, triacsin C, which blocks both triglyceride and cholesterol ester synthesis, cleared most of the lipid droplets in cells. By contrast, YIC-C8-434, which only abrogates production of cholesterol esters, induced an increase in size of droplets. Although both compounds slightly reduced viral RNA synthesis, they significantly impaired assembly of infectious virions in infected cells. In the case of triacsin C, reduced stability of the viral core protein, which forms the virion nucleocapsid and is targeted to the surface of lipid droplets, correlated with lower virion assembly. In addition, the virus particles that were released from cells had reduced specific infectivity. YIC-C8-434 did not alter the association of core with lipid droplets but appeared to decrease production of infectious virus particles, suggesting a block in virion assembly. Thus, the compounds have antiviral properties, indicating that targeting synthesis of lipids stored in lipid droplets might be an option for therapeutic intervention in treating chronic hepatitis C virus infection.

Topics: Cell Line; Cholesterol Esters; Fluorescent Antibody Technique, Indirect; Hepacivirus; Humans; RNA, Viral; Triglycerides; Virion; Virus Assembly

PubMed: 24917668
DOI: 10.1074/jbc.M114.582999

Authors: Rongfei Lu, Jianwei Xu, Zhen Wang...

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

Authors: Yan Liu, Daniel Mihna, Lahoucine Izem...

We previously reported that overexpression of full-length cholesteryl ester transfer protein (FL-CETP), but not its exon 9-deleted variant (∆E9-CETP), in an adipose cell line reduces their triacylglycerol (TAG) content. This provided mechanistic insight into several in vivo studies where FL-CETP levels are inversely correlated with adiposity. However, increased FL-CETP is also associated with elevated hepatic lipids, suggesting that the effect of CETP on cellular lipid metabolism may be tissue-specific. Here, we directly investigated the role of FL-CETP and ∆E9-CETP in hepatic lipid metabolism. FL- or ∆E9-CETP was overexpressed in HepG2-C3A by adenovirus transduction. Overexpression of either FL or ∆E9-CETP in hepatocytes increased cellular TAG mass by 25% but reduced TAG secretion. This cellular TAG was contained in larger and more numerous lipid droplets. Analysis of TAG synthetic and catabolic pathways showed that this elevated TAG content was due to increased incorporation of fatty acid into TAG (24%), and higher de novo synthesis of fatty acid (50%) and TAG from acetate (40%). siRNA knockdown of CETP had the opposite effect on TAG synthesis and lipogenesis, and decreased cellular TAG. This novel increase in cellular TAG by FL-CETP overexpression was reproduced in Caco-2 intestinal epithelial cells. We conclude that, unlike that seen in adipocyte cells, overexpression of either CETP isoform in lipoprotein-secreting cells promotes the accumulation of TAG. These data suggest that the in vivo correlation between CETP levels and hepatic steatosis can be explained, in part, by a direct effect of CETP on hepatocyte cellular metabolism.

Topics: Caco-2 Cells; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Exons; Hep G2 Cells; Hepatocytes; Humans; Triglycerides

PubMed: 34866179
DOI: 10.1002/lipd.12330

Review

Authors: Motohiro Sekiya, Jun-Ichi Osuga, Masaki Igarashi...

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

Comparative Study

Authors: L M Pfeffer, B C Kwok, F R Landsberger...

Treatment of human HeLa-S3 cells (an epidermoid carcinoma line) with human beta-interferon (640 units/ml) selectively alters lipid metabolism by increasing cholesterol synthesis per mg of cell protein as measured by 1-hr pulse-labeling of cells with [3H]acetate. Cholesterol synthesis in interferon-treated cells is increased approximately equal to 60% at 24 hr after the beginning of treatment and approximately equal to 450% at 48 hr. Continuous labeling of interferon-treated cells with [14C]acetate shows increased accumulation of label in cholesterol when normalized per mg of cell protein, as well as an increase in the specific activity of cholesterol in the treated cells. In contrast, interferon treatment decreases the accumulation of [14C]acetate into cholesterol esters. The [14C]acetate labeling of sphingomyelin, phosphatidylethanolamine, and triglycerides shows no change compared to untreated controls. The labeling of phosphatidylcholine was moderately increased in treated cells. The interferon-induced changes in lipid metabolism are a part of a coordinated response of cells to interferon treatment, characterized by reduced cell proliferation and cell motility and an increase in cell size and mass. The increased cholesterol synthesis is consistent with a model in which beta-interferon treatment of HeLa cells inhibits the endocytosis of cholesterol-containing low density lipoprotein, which results in an increase in cholesterol synthesis.

Topics: Acetates; Acetic Acid; Cholesterol; Cholesterol Esters; Endocytosis; HeLa Cells; Humans; Interferon Type I; Kinetics; Lipoproteins, LDL; Phosphatidylcholines

PubMed: 3857592
DOI: 10.1073/pnas.82.8.2417