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Sample records for lipoprotein cholesterol modulated

  1. Characterization of biophysical properties of baboon lipoproteins: modulation by dietary fat and cholesterol

    SciTech Connect

    Babiak, J.

    1984-04-01

    The serum lipoproteins of baboons fed diets containing differing types and amounts of fat and varying amounts of cholesterol were examined by analytic ultracentrifugation, gradient gel electrophoresis, density gradient ultracentrifugation, sodium dodecyl sulfate-polyacrylamide electrophoresis, electron microscopy, and standard protein and lipid composition assays. These studies characterized the lipoproteins of the baboon, observed how concentrations and physical-chemical properties of the lipoproteins are modulated by dietary fat and cholesterol and described the suitability of the baboon as an animal model of human lipoprotein metabolism. Results indicate that baboon high density lipoproteins (HDL), though higher in total serum concentration than human HDL, are remarkably similar to human HDL. The concentration of baboon HDL is increased by dietary saturated fat but decreased by the addition of cholesterol. While serum concentrations of low density lipoproteins (LDL) tend to be lower in baboons, the physical-chemical properties of the LDL of baboons and humans are comparable. The LDL of both species contains apolipoprotein B as their major apolipoprotein and exhibit considerable polydispersity in particle size. LDL of both species consists of seven discrete subpopulations. The analytical and statistical data presented in this dissertation indicate that the baboon is a good model for studying the role of lipoproteins in the development of atherosclerosis. 125 references, 31 figures, 28 tables.

  2. Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism.

    PubMed

    Gunawardane, Ruwanthi N; Fordstrom, Preston; Piper, Derek E; Masterman, Stephanie; Siu, Sophia; Liu, Dongming; Brown, Mike; Lu, Mei; Tang, Jie; Zhang, Richard; Cheng, Janet; Gates, Andrew; Meininger, David; Chan, Joyce; Carlson, Tim; Walker, Nigel; Schwarz, Margrit; Delaney, John; Zhou, Mingyue

    2016-02-01

    Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID:26644477

  3. Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism*

    PubMed Central

    Gunawardane, Ruwanthi N.; Fordstrom, Preston; Piper, Derek E.; Masterman, Stephanie; Siu, Sophia; Liu, Dongming; Brown, Mike; Lu, Mei; Tang, Jie; Zhang, Richard; Cheng, Janet; Gates, Andrew; Meininger, David; Chan, Joyce; Carlson, Tim; Walker, Nigel; Schwarz, Margrit; Delaney, John; Zhou, Mingyue

    2016-01-01

    Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID:26644477

  4. Regulation of Plasma Cholesterol by Lipoprotein Receptors

    NASA Astrophysics Data System (ADS)

    Brown, Michael S.; Kovanen, Petri T.; Goldstein, Joseph L.

    1981-05-01

    The lipoprotein transport system holds the key to understanding the mechanisms by which genes, diet, and hormones interact to regulate the plasma cholesterol level in man. Crucial components of this system are lipoprotein receptors in the liver and extrahepatic tissues that mediate the uptake and degradation of cholesterol-carrying lipoproteins. The number of lipoprotein receptors, and hence the efficiency of disposal of plasma cholesterol, can be increased by cholesterol-lowering drugs. Regulation of lipoprotein receptors can be exploited pharmacologically in the therapy of hypercholesterolemia and atherosclerosis in man.

  5. Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphism...

  6. Understanding Lipoproteins as Transporters of Cholesterol and Other Lipids

    ERIC Educational Resources Information Center

    Biggerstaff, Kyle D.; Wooten, Joshua S.

    2004-01-01

    A clear picture of lipoprotein metabolism is essential for understanding the pathophysiology of atherosclerosis. Many students are taught that low-density lipoprotein-cholesterol is "bad" and high-density lipoprotein-cholesterol is "good." This misconception leads to students thinking that lipoproteins are types of cholesterol rather than…

  7. Cholesterol in serum lipoprotein fractions after spaceflight

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Johnson, Philip C., Jr.; Krauhs, Jane M.; Cintron, Nitza M.

    1988-01-01

    Results are reported from blood-lipid measurements obtained from 125 Space Shuttle crew members before and after space flight. The data are presented in tables and discussed in detail. The main differences noted between preflight and postflight values are a 12.8-percent decrease in high-density lipoproteins on postflight day 1 and significant decreases in total cholesterol and both high- and low-density lipoproteins later in the 23-day postflight period.

  8. Total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol and coronary heart disease in Scotland.

    PubMed Central

    Hargreaves, A D; Logan, R L; Thomson, M; Elton, R A; Oliver, M F; Riemersma, R A

    1991-01-01

    OBJECTIVE--To investigate long term changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations and in measures of other risk factors for coronary heart disease and to assess their importance for the development of coronary heart disease in Scottish men. DESIGN--Longitudinal study entailing follow up in 1988-9 of men investigated during a study in 1976. SETTING--Edinburgh, Scotland. SUBJECTS--107 men from Edinburgh who had taken part in a comparative study of risk factors for heart disease with Swedish men in 1976 when aged 40. INTERVENTION--The men were invited to attend a follow up clinic in 1988-9 for measurement of cholesterol concentrations and other risk factor measurements. Eighty three attended and 24 refused to or could not attend. MAIN OUTCOME MEASURES--Changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations, body weight, weight to height index, prevalence of smoking, and alcohol intake; number of coronary artery disease events. RESULTS--Mean serum total cholesterol concentration increased over the 12 years mainly due to an increase in the low density lipoprotein cholesterol fraction (from 3.53 (SD 0.09) to 4.56 (0.11) mmol/l) despite a reduction in high density lipoprotein cholesterol concentration. Body weight and weight to height index increased. Fewer men smoked more than 15 cigarettes/day in 1988-9 than in 1976. Blood pressure remained stable and fasting triglyceride concentrations did not change. The frequency of corneal arcus doubled. Alcohol consumption decreased significantly. Eleven men developed clinical coronary heart disease. High low density lipoprotein and low high density lipoprotein cholesterol concentrations in 1976, but not total cholesterol concentration, significantly predicted coronary heart disease (p = 0.05). Almost all of the men who developed coronary heart disease were smokers (91% v 53%, p less than

  9. The relationship among brain natriuretic peptide (BNP), cholesterol and lipoprotein

    PubMed Central

    Takeuchi, Hidekazu; Sata, Masataka

    2012-01-01

    Objective To study the relationship among brain natriuretic peptide (BNP), cholesterol and lipoprotein. Design A retrospective, cross-sectional study. Setting Tokushima University Hospital area. Patients A retrospective study of 46 patients (nine inpatients and 37 outpatients) with angina pectoris or arrhythmias who were seen at Tokushima University Hospital Cardiovascular Division and had measurements of their BNP, fatty acid and lipid profile. The average age of patients was 57±17 years, and 39% were male subjects. Main outcome measures BNP, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), apolipoproteinA1, apolipoprotein A2 (ApoA2), apolipoprotein B (ApoB), apolipoprotein C2, apolipoprotein C3, apolipoprotein E, total cholesterol (TC), triglyceride, high density lipoprotein cholesterol and low density lipoprotein cholesterol. Results The baseline characteristics of the patients were shown in table 1 and the data of lipoprotein were shown in table 2. Table 3 shows the relationship among BNP, cholesterol and lipoprotein. The authors found significant negative correlation between serum levels of BNP and ApoA2 (figure 1; r=−0.458, p=0.001), serum levels of BNP and ApoB (figure 2; r=−0.328, p=0.026) and serum levels of BNP and TC (figure 3; r=-0.383, p=0.010). There is a possibility that dietary EPA and DHA may modulate cardiac mitochondrial and autonomic nervous system dysfunction via fatty-acids-PPARs-PTEN-PI3K/Akt-SREBPs system and affect serum BNP levels indirectly. Conclusion BNP had significant negative correlation with ApoA2, ApoB and TC. The findings suggest that increasing serum levels of ApoA2, ApoB and TC may have an effect on improving heart function. But the mechanism is presently unclear. PMID:27326018

  10. Limitations of automated remnant lipoprotein cholesterol assay for diagnostic use

    Technology Transfer Automated Retrieval System (TEKTRAN)

    I wish to comment on the limitations of automated remnant lipoprotein cholesterol (RemL-C) assay reported in Clinical Chemistry. Remnants are lipoprotein particles produced after newly formed triglyceride-rich lipoproteins (TRLs) of either hepatic or intestinal origin enter the plasma space and unde...

  11. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease and blood triglycerides reflect key metabolic processes including sensitivity to insulin. Blood lipoprotein and lipid concentrations are heritable. To date, the identification o...

  12. Rapid labeling of lipoproteins in plasma with radioactive cholesterol. Application for measurement of plasma cholesterol esterification

    SciTech Connect

    Yen, F.T.; Nishida, T. )

    1990-02-01

    In order to efficiently and rapidly label lipoproteins in plasma with ({sup 3}H)cholesterol, micelles consisting of lysophosphatidylcholine (lysoPC) and ({sup 3}H)cholesterol (molar ratio, 50:1) were prepared. When trace amounts of these micelles were injected into plasma, ({sup 3}H)cholesterol rapidly equilibrated among the plasma lipoproteins, as compared to ({sup 3}H)cholesterol from an albumin-stabilized emulsion. The distributions of both ({sup 3}H)cholesterol and unlabeled free cholesterol in plasma lipoproteins were similar in labeled plasma samples. This method of labeling can be used for the measurement of cholesterol esterification, or lecithin:cholesterol acyltransferase activity, in small amounts (20-40 microliters) of plasma samples.

  13. [A history and review of cholesterol ester transfer protein inhibitors and their contribution to the understanding of the physiology and pathophysiology of high density lipoprotein].

    PubMed

    Corral, Pablo; Schreier, Laura

    2014-01-01

    There is irrefutable evidence that statins reduce the risk of cardiovascular events in a magnitude proportional to the intensity of the decrease in cholesterol transport by the low density lipoproteins. Despite this great advance there is still a residual risk of cardiovascular events. For this reason, an increase in the levels of high density lipoprotein is considered in order to boost the main action of this lipoprotein, which is reverse cholesterol transport. Distinct classes of evidence (epidemiological, genetic, and pathophysiological) show that the inhibition and/or modulation of cholesterol ester transfer protein increases plasma high density lipoprotein-cholesterol levels. The main reason for presenting this review is to look at the physiology of cholesterol ester transfer protein, its interrelationship with high density lipoproteins, and to give an update on the development of different cholesterol ester transfer protein inhibitor/modulator molecules. PMID:24094503

  14. Lipoprotein products of lecithin: cholesterol acyltransferase and cholesteryl ester transfer.

    PubMed

    Rose, H G; Ellerbe, P

    1982-09-14

    High-density lipoprotein substrates and products of human plasma lecithin: cholesterol acyltransferase have been labelled with radioisotopic cholesteryl esters in order to facilitate identification. [3H]Cholesteryl esters were formed by endogenous HDL3/VHDL enzyme (d greater than 1.125 g/ml) following incubation with mixed vesicles of phosphatidylcholine, unesterified cholesterol and 3H-labelled unesterified cholesterol. Transfer of labelled esters to acceptor lipoproteins (VLDL+LDL, d less than 1.063 g/ml) was employed to distinguish a hypothetical transfer complex. Separation of labelled HDL3/VHDL was by gel-permeation chromatography. The results indicate that a subpopulation of labelled HDL3/VHDL cholesteryl esters (43-61% of total) were removed by VLDL/LDL during a 3 h transfer period and these derive from the smaller lipoproteins of the spectrum. HDL carrying non-transferable [3H]cholesteryl esters localize to the larger HDL3. Transfer rates were proportional to ratios of acceptor to donor lipoproteins. Net transfer of cholesteryl esters from the smaller HDL3 also occurred, but was smaller in magnitude (about 10.5% of total). Acyltransferase assays indicated that enzyme distribution is skewed to larger-sized HDL3, suggesting that the non-transferable components might be lecithin: cholesterol acyltransferase-containing parent complexes, while the smaller transfer products contain little acyltransferase. The results fit the hypothesis that a parent HDL3-lecithin: cholesterol acyltransferase complex generates a smaller-sized lipoprotein product which is active in cholesteryl ester transport. PMID:7126623

  15. Cholesterol transfer from normal and atherogenic low density lipoproteins to Mycoplasma membranes

    SciTech Connect

    Mitschelen, J.J.; St. Clair, R.W.; Hester, S.H.

    1981-01-01

    The purpose of this study was to determine whether the free cholesterol of hypercholesterolemic low density lipoprotein from cholesterol-fed nonhuman primates has a greater potential for surface transfer to cell membranes than does the free cholesterol of normal low density lipoprotein. The low density lipoproteins were isolated from normal and hypercholesterolemic rhesus and cynomolgus monkeys, incubated with membranes from Acholeplasma laidlawii, a mycoplasma species devoid of cholesterol in its membranes, and the mass transfer of free cholesterol determined by measuring membrane cholesterol content. Since these membranes neither synthesize nor esterify cholesterol, nor degrade the protein or cholesterol ester moieties of low density lipoprotein, they are an ideal model with which to study differences in the cholesterol transfer potential of low density lipoprotein independent of the uptake of the intact low density lipoprotein particle. These studies indicate that, even though there are marked differences in the cholesterol composition of normal and hypercholesterolemic low density lipoproteins, this does not result in a greater chemical potential for surface transfer of free cholesterol. Consequently, if a difference in the surface transfer of free cholesterol is responsible for the enhanced ability of hypercholesterolemic low density lipoprotein to promote cellular cholesterol accumulation and, perhaps, also atherosclerosis, it must be the result of differences in the interaction to the hypercholesterolemic low density lipoprotein with the more complicated mammalian cell membranes, rather than differences in the chemical potential for cholesterol transfer.

  16. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis

    PubMed Central

    Ossoli, Alice; Pavanello, Chiara

    2016-01-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  17. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis.

    PubMed

    Ossoli, Alice; Pavanello, Chiara; Calabresi, Laura

    2016-06-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  18. Tailoring of Biomimetic High-Density Lipoprotein (HDL) Nanostructures Changes Cholesterol Binding and Efflux

    PubMed Central

    Luthi, Andrea J.; Zhang, Heng; Kim, Dongwoo; Giljohann, David A.; Mirkin, Chad A.; Thaxton, C. Shad

    2014-01-01

    Gold nanoparticles (Au NPs) were employed as templates to synthesize spherical, high-density lipoprotein (HDL) biomimics (HDL Au NPs) of different sizes and surface chemistries. The effect of size and surface chemistry on the cholesterol binding properties and the ability of the HDL Au NPs to efflux cholesterol from macrophage cells were measured. Results demonstrate that Au NPs may be utilized as templates to generate nanostructures with different physical characteristics that mimic natural HDL. Furthermore, the properties of the HDL Au NPs may be tailored to modulate the ability to bind cholesterol in solution and efflux cholesterol from macrophages. From the conjugates tested, the optimum size and surface chemistry for preparing functional Au NP-templated HDL biomimics were identified. PMID:22117189

  19. Acrolein Impairs the Cholesterol Transport Functions of High Density Lipoproteins

    PubMed Central

    Chadwick, Alexandra C.; Holme, Rebecca L.; Chen, Yiliang; Thomas, Michael J.; Sorci-Thomas, Mary G.; Silverstein, Roy L.; Pritchard, Kirkwood A.; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway. PMID:25849485

  20. High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need

    PubMed Central

    Cimmino, Giovanni; Ciccarelli, Giovanni; Morello, Alberto; Ciccarelli, Michele; Golino, Paolo

    2015-01-01

    Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies. PMID:26535185

  1. Ethanol enhances de novo synthesis of high density lipoprotein cholesterol

    SciTech Connect

    Cluette, J.E.; Mulligan, J.J.; Noring, R.; Doyle, K.; Hojnacki, J.

    1984-05-01

    Male squirrel monkeys fed ethanol at variable doses were used to assess whether alcohol enhances de novo synthesis of high density lipoprotein (HDL) cholesterol in vivo. Monkeys were divided into three groups: 1) controls fed isocaloric liquid diet; 2) low ethanol monkeys fed liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) High Ethanol animals fed diet plus vodka at 24% of calories. High Ethanol primates had significantly higher levels of HDL nonesterified cholesterol than Control and Low Ethanol animals while serum glutamate oxaloacetate transaminase was similar for the three treatments. There were no significant differences between the groups in HDL cholesteryl ester mass or specific activity following intravenous injection of labeled mevalonolactone. By contrast, High Ethanol monkeys had significantly greater HDL nonesterified cholesterol specific activity with approximately 60% of the radioactivity distributed in the HDL/sub 3/ subfraction. This report provides the first experimental evidence that ethanol at 24% of calories induces elevations in HDL cholesterol in primates through enhanced de novo synthesis without adverse effects on liver function.

  2. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

    SciTech Connect

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J.

    2014-09-05

    Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

  3. Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.

    PubMed

    Mahley, Robert W

    2016-07-01

    ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease. PMID:27174096

  4. Furin-cleaved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Active and Modulates Low Density Lipoprotein Receptor and Serum Cholesterol Levels

    PubMed Central

    Lipari, Michael T.; Li, Wei; Moran, Paul; Kong-Beltran, Monica; Sai, Tao; Lai, Joyce; Lin, S. Jack; Kolumam, Ganesh; Zavala-Solorio, Jose; Izrael-Tomasevic, Anita; Arnott, David; Wang, Jianyong; Peterson, Andrew S.; Kirchhofer, Daniel

    2012-01-01

    Proprotein convertase subtilisin/kexin 9 (PCSK9) regulates plasma LDL cholesterol levels by regulating the degradation of LDL receptors. Another proprotein convertase, furin, cleaves PCSK9 at Arg218-Gln219 in the surface-exposed “218 loop.” This cleaved form circulates in blood along with the intact form, albeit at lower concentrations. To gain a better understanding of how cleavage affects PCSK9 function, we produced recombinant furin-cleaved PCSK9 using antibody Ab-3D5, which binds the intact but not the cleaved 218 loop. Using Ab-3D5, we also produced highly purified hepsin-cleaved PCSK9. Hepsin cleaves PCSK9 at Arg218-Gln219 more efficiently than furin but also cleaves at Arg215-Phe216. Further analysis by size exclusion chromatography and mass spectrometry indicated that furin and hepsin produced an internal cleavage in the 218 loop without the loss of the N-terminal segment (Ser153–Arg218), which remained attached to the catalytic domain. Both furin- and hepsin-cleaved PCSK9 bound to LDL receptor with only 2-fold reduced affinity compared with intact PCSK9. Moreover, they reduced LDL receptor levels in HepG2 cells and in mouse liver with only moderately lower activity than intact PCSK9, consistent with the binding data. Single injection into mice of furin-cleaved PCSK9 resulted in significantly increased serum cholesterol levels, approaching the increase by intact PCSK9. These findings indicate that circulating furin-cleaved PCSK9 is able to regulate LDL receptor and serum cholesterol levels, although somewhat less efficiently than intact PCSK9. Therapeutic anti-PCSK9 approaches that neutralize both forms should be the most effective in preserving LDL receptors and in lowering plasma LDL cholesterol. PMID:23135270

  5. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase.

    PubMed

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M; Brown, Robert J

    2014-09-01

    Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL. PMID:25130461

  6. Metabolism of low-density lipoprotein free cholesterol by human plasma lecithin-cholesterol acyltransferase

    SciTech Connect

    Fielding, P.E.; Miida, Takashi; Fielding, C.J. )

    1991-09-03

    The metabolism of cholesterol derived from ({sup 3}H) cholesterol-labeled low-density lipoprotein (LDL) was determined in human blood plasma. LDL-derived free cholesterol first appeared in large {alpha}-migrating HDL (HDL{sub 2}) and was then transferred to small {alpha}-HDL (HDL{sub 3}) for esterification. The major part of such esters was retained within HDL of increasing size in the course of lecithin-cholesterol acyltransferase (LCAT) activity; the balance was recovered in LDL. Transfer of preformed cholesteryl esters within HDL contributed little to the labeled cholesteryl ester accumulating HDL{sub 2}. When cholesterol for esterification was derived instead from cell membranes, a significantly smaller proportion of this cholesteryl ester was subsequently recovered in LDL. These data suggest compartmentation of cholesteryl esters within plasma that have been formed from cell membrane or LDL free cholesterol, and the role for HDL{sub 2} as a relatively unreactive sink for LCAT-derived cholesteryl esters.

  7. Relative atherogenicity and predictive value of non-high-density lipoprotein cholesterol for coronary heart disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although low-density lipoprotein cholesterol (LDL-C) is a well-established atherogenic factor for coronary heart disease, it does not completely represent the risk associated with atherogenic lipoproteins in the presence of high triglyceride (TG) levels. Constituent lipoproteins constituting non–hig...

  8. Membrane Cholesterol Modulates Superwarfarin Toxicity.

    PubMed

    Marangoni, M Natalia; Martynowycz, Michael W; Kuzmenko, Ivan; Braun, David; Polak, Paul E; Weinberg, Guy; Rubinstein, Israel; Gidalevitz, David; Feinstein, Douglas L

    2016-04-26

    Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content. PMID:27119638

  9. The Role of Dietary Cholesterol in Lipoprotein Metabolism and Related Metabolic Abnormalities: A Mini-review.

    PubMed

    Kapourchali, Fatemeh Ramezani; Surendiran, Gangadaran; Goulet, Amy; Moghadasian, Mohammed H

    2016-10-25

    Cholesterol plays a vital role in cell biology. Dietary cholesterol or "exogenous" cholesterol accounts for approximately one-third of the pooled body cholesterol, and the remaining 70% is synthesized in the body (endogenous cholesterol). Increased dietary cholesterol intake may result in increased serum cholesterol in some individuals, while other subjects may not respond to dietary cholesterol. However, diet-increased serum cholesterol levels do not increase the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, nor do they decrease the size of LDL particles or HDL cholesterol levels. Elevated levels of LDL cholesterol, reduced HDL cholesterol levels, and small, dense LDL particles are independent risk factors for coronary artery disease. Dietary cholesterol is the primary approach for treatment of conditions such as the Smith-Lemli-Opitz syndrome. Recent studies have highlighted mechanisms for absorption of dietary cholesterol. These studies have help understand how dietary and/or pharmaceutical agents inhibit cholesterol absorption and thereby reduce LDL cholesterol concentrations. In this article, various aspects of cholesterol metabolism, including dietary sources, absorption, and abnormalities in cholesterol metabolism, have been summarized and discussed. PMID:26055276

  10. Lysosomal Cholesterol Accumulation Inhibits Subsequent Hydrolysis Of Lipoprotein Cholesteryl Ester

    PubMed Central

    Jerome, W. Gray; Cox, Brian E.; Griffin, Evelyn E.; Ullery, Jody C.

    2010-01-01

    Human macrophages incubated for prolonged periods with mildly oxidized LDL (oxLDL) or cholesteryl ester-rich lipid dispersions (DISP) accumulate free and esterified cholesterol within large, swollen lysosomes similar to those in foam cells of atherosclerosis. The cholesteryl ester (CE) accumulation is, in part, the result of inhibition of lysosomal hydrolysis due to increased lysosomal pH mediated by excessive lysosomal free cholesterol (FC). To determine if the inhibition of hydrolysis was long lived and further define the extent of the lysosomal defect, we incubated THP-1 macrophages with oxLDL or DISP to produce lysosome sterol engorgement and then chased with acetylated LDL (acLDL). Unlike oxLDL or DISP, CE from acLDL normally is hydrolyzed rapidly. Three days of incubation with oxLDL or DISP produced an excess of CE in lipid-engorged lysosomes, indicative of inhibition. After prolonged oxLDL or DISP pretreatment, subsequent hydrolysis of acLDL CE was inhibited. Coincident with the inhibition, the lipid-engorged lysosomes failed to maintain an acidic pH during both the initial pretreatment and subsequent acLDL incubation. This indicates that the alterations in lysosomes were general, long-lived and affected subsequent lipoprotein metabolism. This same phenomenon, occurring within atherosclerotic foam cells, could significantly affect lesion progression. PMID:18312718

  11. Dietary cholesterol and plasma lipoprotein profiles: Randomized controlled trials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early work suggested that dietary cholesterol increased plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk, dietary guidelines have consistently recommended limiting food sources of cholesterol....

  12. Novel Therapies for Low-Density Lipoprotein Cholesterol Reduction.

    PubMed

    Toth, Peter P

    2016-09-15

    Although many clinical trials and meta-analyses have demonstrated that lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with proportionately greater reductions in the risk of cardiovascular disease events, not all patients with hypercholesterolemia are able to attain risk-stratified LDL-C goals with statin monotherapy. Elucidation of the pathophysiology of genetic disorders of lipid metabolism (e.g., familial hypercholesterolemia) has led to the development of several novel lipid-lowering strategies, including blocking the degradation of hepatic LDL-C receptors that are important in LDL-C clearance, or the inhibition of apoprotein synthesis and lipidation. Mipomersen and lomitapide are highly efficacious new agents available for the treatment of patients with homozygous familial hypercholesterolemia. The recent introduction of PCSK9 inhibitors (alirocumab and evolocumab) have made it possible for many patients to achieve very low LDL-C concentrations (e.g., <40 mg/dl) that are usually not attainable with statin monotherapy. Ongoing clinical trials are examining the impact of very low LDL-C levels on cardiovascular disease event rates and the long-term safety of this approach. PMID:27620356

  13. High-density lipoprotein cholesterol on a roller coaster: where will the ride end?

    PubMed

    Kronenberg, Florian

    2016-04-01

    Bowe et al. report an association between low high-density lipoprotein cholesterol concentrations and various incident chronic kidney disease end points in a cohort of almost 2 million US veterans followed for 9 years. These impressive data should be a starting point for further investigations including genetic epidemiologic investigations as well as post hoc analyses of interventional trials that target high-density lipoprotein cholesterol and, finally, studies that focus on the functionality of high-density lipoprotein particles. PMID:26994572

  14. Receptor-mediated uptake of remnant lipoproteins by cholesterol-loaded human monocyte-macrophages

    SciTech Connect

    Van Lenten, B.J.; Fogelman, A.M.; Jackson, R.L.; Shapiro, S.; Haberland, M.E.; Edwards, P.A.

    1985-07-25

    Normal human monocyte-macrophages were cholesterol-loaded, and the rates of uptake and degradation of several lipoproteins were measured and compared to rates in control cells. Receptor activities for SVI-rabbit beta-very low density lipoproteins (beta-VLDL), SVI-human low density lipoprotein, and SVI-human chylomicrons were down-regulated in cholesterol-loaded cells; however, the rate of uptake and degradation of SVI-human chylomicron remnants was unchanged from control cells. Cholesterol-loaded alveolar macrophages from a Watanabe heritable hyperlipidemic rabbit, which lack low density lipoprotein receptors, showed receptor down-regulation for SVI-beta-VLDL but not for SVI-human chylomicron remnants. In addition to chylomicron remnants, apo-E-phospholipid complexes competed for SVI-chylomicron remnant uptake, but apo-A-I-phospholipid complexes did not. Chylomicron remnants and beta-VLDL were equally effective in competing for SVI-beta-VLDL and SVI-chylomicron remnant uptake in cholesterol-loaded macrophages. The authors conclude: 1) specific lipoprotein receptor activity persists in cholesterol-loaded cells; 2) this receptor activity recognizes lipo-proteins (at least in part) by their apo-E content; and 3) cholesteryl ester accumulation can occur in monocyte-macrophages incubated with chylomicron remnants.

  15. [Lipoproteins].

    PubMed

    Manso, C

    1991-02-01

    The problem of plasma lipid transport between several organs is reviewed. The constitution of plasma lipoproteins is described as well as the importance of enzymes related to them. The problem of lipid transfer proteins is discussed. The origin of atherosclerosis is analyzed in relation to abnormalities of cholesterol metabolism, of its transport and of free radicals generation. PMID:2059473

  16. Lipoprotein Subfraction Cholesterol Distribution Is Proatherogenic in Women With Type 1 Diabetes and Insulin Resistance

    PubMed Central

    Maahs, David M.; Hokanson, John E.; Wang, Hong; Kinney, Gregory L.; Snell-Bergeon, Janet K.; East, Ashley; Bergman, Bryan C.; Schauer, Irene E.; Rewers, Marian; Eckel, Robert H.

    2010-01-01

    OBJECTIVE Individuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk. RESEARCH DESIGN AND METHODS Fast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp. RESULTS Among men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes. CONCLUSIONS The expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes. PMID:20393149

  17. Reliability of Calculated Low-Density Lipoprotein Cholesterol.

    PubMed

    Meeusen, Jeffrey W; Snozek, Christine L; Baumann, Nikola A; Jaffe, Allan S; Saenger, Amy K

    2015-08-15

    Aggressive low-density lipoprotein cholesterol (LDL-C)-lowering strategies are recommended for prevention of cardiovascular events in high-risk populations. Guidelines recommend a 30% to 50% reduction in at-risk patients even when LDL-C concentrations are between 70 and 130 mg/dl (1.8 to 3.4 mmol/L). However, calculation of LDL-C by the Friedewald equation is the primary laboratory method for routine LDL-C measurement. We compared the accuracy and reproducibility of calculated LDL-C <130 mg/dl (3.4 mmol/L) to LDL-C measured by β quantification (considered the gold standard method) in 15,917 patients with fasting triglyceride concentrations <400 mg/dl (4.5 mmol/L). Both variation and bias of calculated LDL-C increased at lower values of measured LDL-C. The 95% confidence intervals for a calculated LDL-C of 70 mg/dl (1.8 mmol/L) and 30 mg/dl (0.8 mmol/L) were 60 to 86 mg/dl (1.6 to 2.2 mmol/L) and 24 to 60 mg/dl (0.6 to 1.6 mmol/L), respectively. Previous recommendations have emphasized the requirement for a fasting sample with triglycerides <400 mg/dl (4.5 mmol/L) to calculate LDL-C by the Friedewald equation. However, no recommendations have addressed the appropriate lower reportable limit for calculated LDL-C. In conclusion, calculated LDL-C <30 mg/dl (0.8 mmol/L) should not be reported because of significant deviation from the gold standard measured LDL-C results, and caution is advised when using calculated LDL-CF values <70 mg/dl (1.8 mmol/L) to make treatment decisions. PMID:26059865

  18. Psyllium husk. I: Effect on plasma lipoproteins, cholesterol metabolism, and atherosclerosis in African green monkeys.

    PubMed

    McCall, M R; Mehta, T; Leathers, C W; Foster, D M

    1992-08-01

    Psyllium's effects on plasma and lipoprotein cholesterol concentrations, cholesterol metabolism, and diet-induced atherosclerosis were studied in adult male African green monkeys (Cercopithecus aethiops). Animals were fed for 3.5 y one of three experimental diets: low-cholesterol cellulose (LCC), high-cholesterol cellulose (HCC), or high-cholesterol psyllium (HCP). The LCC and HCP groups had significantly (P less than 0.05) lower plasma cholesterol concentrations (39% lower) at 1 mo than did the HCC group. These responses persisted throughout the study. Plasma cholesterol changes were due to a reduction in intermediate-density and low-density lipoproteins; very-low and high-density-lipoprotein concentrations were similar among groups. Aortic atherosclerosis, evaluated as percent sudanophilia at 3.5 y, was lowest in the LCC group, intermediate in the HCP group, and highest in the HCC group. Cholesterol absorption, neutral steroid and fat excretion, HMGCoA reductase activity (in intestine and liver), and body weight were unrelated to psyllium's hypocholesterolemic effects. PMID:1322032

  19. Effects of zinc and cholesterol/choleate on serum lipoproteins and the liver in rats

    SciTech Connect

    Cho, C.H.; Chen, S.M.; Ogle, C.W.; Young, T.K.

    1989-01-01

    The effects of short-term treatment with orally-administered zinc sulfate and/or a mixture of cholesterol/choleate on serum lipoprotein and hepatic enzyme levels were studied. Administration of graded doses of zinc sulfate for 5 days, dose-dependently increased serum and hepatic zinc levels but depressed the serum high-density lipoprotein-cholesterol (HDL-C) concentration and liver cytochrome P-450 activity. However, it did not affect hepatic concentrations of malondialdehyde and free {beta}-glucuronidase. Cholesterol/choleate treatment for 5 days markedly damaged the liver, as reflected by elevations of hepatic concentrations of malondialdehyde (both in the mitochondrial and microsomal fractions) and of free {beta}-glucuronidase; total cholesterol and low-density lipoprotein-cholesterol in the blood were increased, whereas HDL-C was decreased significantly. Concomitant administration of zinc sulfate with cholesterol/choleate further lowered HDL-C levels, but reversed the high hepatic concentrations of both malondialdehyde and free {beta}-glucuronidase. The present study indicates that both zinc ions and cholesterol can decrease circulatory HDL-C levels and that zinc protects against cholesterol-induced hepatic damage by reducing lysosomal enzyme release and preventing lipid peroxidation in the liver.

  20. Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis.

    PubMed

    Carter, C J

    2007-01-01

    Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to

  1. Very old adults with better memory function have higher low-density lipoprotein cholesterol levels and lower triglyceride to high-density lipoprotein cholesterol ratios: KOCOA project

    PubMed Central

    Katsumata, Yuriko; Todoriki, Hidemi; Higashiuesato, Yasushi; Yasura, Shotoku; Ohya, Yusuke; Willcox, D. Craig; Dodge, Hiroko H.

    2013-01-01

    We examined cross-sectionally which lipid profiles are associated with better cognitive function among those aged 80 and older-free of dementia (Clinical Dementia Rating ≤ 0.5), functionally independent and community-dwelling. Our cohort consisted of 193 participants from the “Keys to Optimal Cognitive Aging (KOCOA) Project”, a prospective cohort study in Okinawa, Japan. Higher low-density lipoprotein cholesterol levels and lower triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratios were associated with higher scores in memory performance after controlling for confounders. Further research is required to clarify the associations among LDL-C levels, TG/HDL-C ratios, and healthy cognitive aging. PMID:23207484

  2. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels

    PubMed Central

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S.; Still, Christopher D.; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R.; Pollin, Toni I.; Angles-Cano, Eduardo; Quon, Michael J.; Mitchell, Braxton D.; Shuldiner, Alan R.; Fu, Mao

    2015-01-01

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68–0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5–APOA4–APOC3–APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10−8 to 3.91 × 10−19) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10−14) and rs10455872 (P = 1.85 × 10−12). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10−9). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation. PMID:25575512

  3. Associations between Serum 25-hydroxyvitamin D and Lipids, Lipoprotein Cholesterols, and Homocysteine

    PubMed Central

    Glueck, Charles J.; Jetty, Vybhav; Rothschild, Matan; Duhon, Gregory; Shah, Parth; Prince, Marloe; Lee, Kevin; Goldenberg, Michael; Kumar, Ashwin; Goldenberg, Naila; Wang, Ping

    2016-01-01

    Background: Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine. Aims: In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine. Materials and Methods: We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI. Results: Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R2 =3.6%), triglyceride (partial R2 =3.1%), and LDLC (partial R2 =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R2 = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R2 = 6.0–12.6%). Conclusions: In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant

  4. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study.

    PubMed Central

    Lindenstrøm, E.; Boysen, G.; Nyboe, J.

    1994-01-01

    OBJECTIVE--To estimate the influence of plasma total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. DESIGN--The Copenhagen City Heart Study is a prospective observational survey with two cardiovascular examinations at five year intervals. Non-fasting plasma lipids were measured in participants once at each examination, along with other variables. The Cox regression model was used to establish the effect of the factors recorded on cerebrovascular events of mostly, but not exclusively, ischaemic origin. SUBJECTS--19,698 women and men at least 20 years old, randomly selected after age stratification from an area of central Copenhagen. MAIN OUTCOME MEASURES--Initial cases of stroke and transient ischaemic attack recorded from hospital records and death certificates from 1976 through 1988. RESULTS--660 non-haemorrhagic and 33 haemorrhagic events were recorded. Total cholesterol was positively associated with risk of non-haemorrhagic events, but only for levels > 8 mmol/l, corresponding to the upper 5% of the distribution in the study population. For lower plasma cholesterol values the relative risk remained nearly constant. Plasma triglyceride concentration was significantly, positively associated with risk of non-haemorrhagic events. The relative risk corresponding to an increase of 1 mmol/l was 1.12 (95% confidence interval 1.07 to 1.16). There was a negative, log linear association between high density lipoprotein cholesterol and risk of non-haemorrhagic events (0.53 (0.34 to 0.83)). There was no indication that the effects of plasma lipids were different in women and men. CONCLUSIONS--The pattern of the association between plasma cholesterol and risk of ischaemic cerebrovascular disease was not log linear, and the increased risk was confined to the upper 5% of the cholesterol distribution. Further studies should concentrate on the association between plasma cholesterol and verified haemorrhagic stroke. PMID

  5. Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality.

    PubMed

    Barylski, Marcin; Toth, Peter P; Nikolic, Dragana; Banach, Maciej; Rizzo, Manfredi; Montalto, Giuseppe

    2014-06-01

    High-density lipoprotein (HDL) particles are highly complex polymolecular aggregates capable of performing a remarkable range of atheroprotective functions. Considerable research is being performed throughout the world to develop novel pharmacologic approaches to: (1) promote apoprotein A-I and HDL particle biosynthesis; (2) augment capacity for reverse cholesterol transport so as to reduce risk for the development and progression of atherosclerotic disease; and (3) modulate the functionality of HDL particles in order to increase their capacity to antagonize oxidation, inflammation, thrombosis, endothelial dysfunction, insulin resistance, and other processes that participate in arterial wall injury. HDL metabolism and the molecular constitution of HDL particles are highly complex and can change in response to both acute and chronic alterations in the metabolic milieu. To date, some of these interventions have been shown to positively impact rates of coronary artery disease progression. However, none of them have as yet been shown to significantly reduce risk for cardiovascular events. In the next 3-5 years a variety of pharmacologic interventions for modulating HDL metabolism and functionality will be tested in large, randomized, prospective outcomes trials. It is hoped that one or more of these therapeutic approaches will result in the ability to further reduce risk for cardiovascular events once low-density lipoprotein cholesterol and non-HDL-cholesterol targets have been attained. PMID:24840270

  6. Age related changes in the lipoprotein substrates for the esterification of plasma cholesterol in rats.

    PubMed

    Lee, S M; Kudchodkar, B J; Lacko, A G

    1991-11-15

    The activity of the enzyme lecithin:cholesterol acyltransferase (LCAT) and the properties of its lipoprotein substrates have been investigated in 6- and 19-month-old Fischer-344 rats. These studies were carried out to determine the nature of the relationship between the observed hypercholesterolemia and the age-related decrease in the fractional rate of lipoprotein cholesterol esterification. The distribution of LCAT activity of plasma fractions was determined following gel chromatography and ultracentrifugation respectively. LCAT activity was found to be associated with the high density lipoprotein (HDL) fraction when rat plasma was passed through a Bio-Gel A-5 M column. Upon density gradient ultracentrifugation for 24 h it was found associated with HDL fraction; d = 1.125-1.21 g/ml. However, following prolonged ultracentrifugation (40 h), the majority of the LCAT activity was displaced into the lipoprotein-free infranatant (d greater than 1.225 g/ml). The dissociation of LCAT from its complex with HDL occurred to a smaller extent in aged rat plasma than in young rat plasma. Substrate specificity studies indicated that HDL was a considerably better substrate for LCAT than very low density lipoproteins (VLDL) in both young and aged rats. In addition, HDL from young rats was a better substrate for LCAT than the HDL from aged rats. Incubation experiments followed by the isolation of lipoproteins and the subsequent analyses of their cholesterol contents revealed that the age-related hypercholesterolemia was mainly due to an increase in the cholesterol carried by lipoprotein fractions d = 1.025 -1.07 g/ml (LDL + HDL1). These and other low density lipoproteins (d less than 1.025 g/ml) were poor substrates for LCAT. However, these lipoproteins could provide free cholesterol for esterification by first transferring it to HDL (d = 1.07-1.21). The HDL isolated from the plasma of aged rats was enriched with apolipoprotein (apo) E and these lipoprotein particles were found to

  7. Effect of apolipoprotein E-free high density lipoproteins on cholesterol metabolism in cultured pig hepatocytes

    SciTech Connect

    Bachorik, P.S.; Virgil, D.G.; Kwiterovich, P.O. Jr.

    1987-10-05

    We studied cholesterol synthesis from (/sup 14/C)acetate, cholesterol esterification from (/sup 14/C)oleate, and cellular cholesterol and cholesteryl ester levels after incubating cells with apoE-free high density lipoproteins (HDL) or low density lipoproteins (LDL). LDL suppressed synthesis by up to 60%, stimulated esterification by up to 280%, and increased cell cholesteryl ester content about 4-fold. Esterification increased within 2 h, but synthesis was not suppressed until after 6 h. ApoE-free HDL suppressed esterification by about 50% within 2 h. Cholesterol synthesis was changed very little within 6 h, unless esterification was maximally suppressed; synthesis was then stimulated about 4-fold. HDL lowered cellular unesterified cholesterol by 13-20% within 2 h and promoted the removal of newly synthesized cholesterol and cholesteryl esters. These changes were transient; by 24 h, both esterification and cellular unesterified cholesterol returned to control levels, and cholesteryl esters increased 2-3-fold. HDL core lipid was taken up selectively from /sup 125/I-labeled (/sup 3/H)cholesteryl ester- and ether-labeled HDL. LDL core lipid uptake was proportional to LDL apoprotein uptake. The findings suggest that 1) the cells respond initially to HDL or LDL with changes in esterification, and 2) HDL mediates both the removal of free cholesterol from the cell and the delivery of HDL cholesteryl esters to the cell.

  8. Impact of Dietary Fat Type Within the Context of Altered Cholesterol Homeostasis on Cholesterol and Lipoprotein Metabolism in the F1B Hamster

    PubMed Central

    Lecker, Jaime L.; Matthan, Nirupa R.; Billheimer, Jeffrey T.; Rader, Daniel J.; Lichtenstein, Alice H.

    2010-01-01

    Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (w/w) coconut, olive or safflower oil with either high cholesterol (0.1%; cholesterol-supplemented) or low cholesterol coupled with cholesterol lowering drugs 10-days prior to killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol-depleted). Irrespective of dietary fat, cholesterol-depletion, relative to supplementation, resulted in lower plasma non-high density lipoprotein (HDL) and HDL cholesterol, and triglyceride concentrations (all P<0.05). In the liver, these differences were associated with higher sterol regulatory element binding protein (SREBP)-2, low density lipoprotein (LDL) receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and 7-α hydroxylase mRNA levels; higher scavenger receptor B1 and apolipoprotein (apo) A-I mRNA and protein levels; and lower apo E protein levels and in intestine modestly lower sterol transporters ATP binding cassette (ABC) A1, ABCG5 and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both P<0.05) and modestly higher SREBP-2 mRNA levels. These data suggest that in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest which limits the usefulness of the experimental animal model. PMID:20197195

  9. Impact of dietary fat type within the context of altered cholesterol homeostasis on cholesterol and lipoprotein metabolism in the F1B hamster.

    PubMed

    Lecker, Jaime L; Matthan, Nirupa R; Billheimer, Jeffrey T; Rader, Daniel J; Lichtenstein, Alice H

    2010-10-01

    Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism, we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (wt/wt) coconut, olive, or safflower oil with either high cholesterol (0.1%; cholesterol supplemented) or low cholesterol coupled with cholesterol-lowering drugs 10 days before killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol depleted). Irrespective of dietary fat, cholesterol depletion, relative to supplementation, resulted in lower plasma non-high-density lipoprotein (non-HDL) and HDL cholesterol, and triglyceride concentrations (all Ps < .05). In the liver, these differences were associated with higher sterol regulatory element binding protein-2, low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 7α-hydroxylase messenger RNA (mRNA) levels; higher scavenger receptor B1 and apolipoprotein A-I mRNA and protein levels; lower apolipoprotein E protein levels; and in intestine, modestly lower sterol transporters adenosine triphosphate-binding cassette (ABC) A1, ABCG5, and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both Ps < .05) and modestly higher sterol regulatory element binding protein-2 mRNA levels. These data suggest that, in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest, which limits the usefulness of the experimental animal model. PMID:20197195

  10. From Evolution to Revolution: miRNAs as Pharmacological Targets for Modulating Cholesterol Efflux and Reverse Cholesterol Transport

    PubMed Central

    Dávalos, Alberto; Fernández-Hernando, Carlos

    2013-01-01

    There has been strong evolutionary pressure to ensure that an animal cell maintain levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies. PMID:23435093

  11. Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...

  12. Direct Low Density Lipoprotein Cholesterol and Glycated Albumin Levels in Type 2 Diabetes Mellitus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) have been associated with a decreased risk of these complications. The aim in this st...

  13. Effects of intensive atorvastatin and rosuvastatin treatment on apolipoprotein B-48 and remnant lipoprotein cholesterol levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Atorvastatin and rosuvastatin at maximal doses are both highly effective in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Rosuvastatin has been shown to be more effective than atorvastatin in lowering LDL-C, small dense LDL-C and in raising high-density lipoprote...

  14. Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis.

    PubMed

    Mercer, Jacob L; Argus, Joseph P; Crabtree, Donna M; Keenan, Melissa M; Wilks, Moses Q; Chi, Jen-Tsan Ashley; Bensinger, Steven J; Lavau, Catherine P; Wechsler, Daniel S

    2015-01-01

    PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer's disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease. PMID:26075887

  15. Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells

    PubMed Central

    Testa, Barbara; Raniolo, Sofia; Fasciglione, Giovanni Francesco; Coletta, Massimiliano; Biocca, Silvia

    2015-01-01

    The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding. PMID:26495844

  16. Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells.

    PubMed

    Gioia, Magda; Vindigni, Giulia; Testa, Barbara; Raniolo, Sofia; Fasciglione, Giovanni Francesco; Coletta, Massimiliano; Biocca, Silvia

    2015-01-01

    The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding. PMID:26495844

  17. The clinical significance of preoperative serum cholesterol and high-density lipoprotein-cholesterol levels in hepatocellular carcinoma

    PubMed Central

    Jiang, Shan-Shan; Weng, De-Sheng; Jiang, Long; Zhang, Yao-Jun; Pan, Ke; Pan, Qiu-Zhong; Chen, Chang-Long; Zhao, Jing-Jing; Zhang, Xiao-Fei; Zhang, Hong-Xia; Tang, Yan; Zhou, Zi-Qi; Chen, Min-Shan; Xia, Jian-Chuan

    2016-01-01

    Purpose: To evaluate the prognostic role of the preoperative plasma lipid profile, including low-density lipoprotein -cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], cholesterol, and triglycerides, in hepatocellular carcinoma patients undergoing radical resection. Methods: Clinical data, including the preoperative plasma profile levels, were retrospectively collected and reviewed in 1411 hepatocellular carcinoma patients, who underwent operation between 2001 and 2010. Kaplan-Meier method and the Cox proportional hazards regression model were used in analyzing the DFS and OS. Results: We found that HDL-C ≤ 0.88 mmol/L and cholesterol ≤ 4.420 mmol/L were preoperative risk factors of disease-free survival (DFS) and overall survival (OS). A decreased CHO level was significantly associated with decreased OS (HR, 0.800; 95% CI, (0.691-0.926), P =0.003) and decreased DFS (HR, 0.844; 95% CI, 0.737-0.966, P=0.012). Additionally, an increased HDL-C level was shown significant association with increased OS (HR, 0.679; 95% CI, 0.570-0.808, P<0.01) and DFS (HR, 2.085; 95% CI, 1.271- 3.422, P = 0.002). In the univariate and multivariate analyses involving OS and DFS, no significant relativity were observed between the LDL-C and TG groups. Conclusions: Decreased levels of CHO and HDL might predict worse outcomes both DFS and OS for hepatocellular carcinoma patients. PMID:27076843

  18. Practical technique to quantify small, dense low-density lipoprotein cholesterol using dynamic light scattering

    NASA Astrophysics Data System (ADS)

    Trirongjitmoah, Suchin; Iinaga, Kazuya; Sakurai, Toshihiro; Chiba, Hitoshi; Sriyudthsak, Mana; Shimizu, Koichi

    2016-04-01

    Quantification of small, dense low-density lipoprotein (sdLDL) cholesterol is clinically significant. We propose a practical technique to estimate the amount of sdLDL cholesterol using dynamic light scattering (DLS). An analytical solution in a closed form has newly been obtained to estimate the weight fraction of one species of scatterers in the DLS measurement of two species of scatterers. Using this solution, we can quantify the sdLDL cholesterol amount from the amounts of the low-density lipoprotein cholesterol and the high-density lipoprotein (HDL) cholesterol, which are commonly obtained through clinical tests. The accuracy of the proposed technique was confirmed experimentally using latex spheres with known size distributions. The applicability of the proposed technique was examined using samples of human blood serum. The possibility of estimating the sdLDL amount using the HDL data was demonstrated. These results suggest that the quantitative estimation of sdLDL amounts using DLS is feasible for point-of-care testing in clinical practice.

  19. A Leap above Friedewald Formula for Calculation of Low-Density Lipoprotein-Cholesterol

    PubMed Central

    Kapoor, Reema; Chakraborty, Montosh; Singh, Navpreet

    2015-01-01

    Purpose: The purpose was to compare the different calculated methods of low-density lipoprotein cholesterol (LDL-C) estimation and to determine which of them correlate best with the direct method. Materials and Methods: The records of 480 samples for lipid profile were analyzed. Apart from the direct method, LDL-C was calculated by Friedewald low-density lipoprotein cholesterol method (F-LDL-C), modified Friedewald low-density lipoprotein cholesterol method (MF-LDL-C), and Anandaraja low-density lipoprotein cholesterol method (A-LDL-C). Paired t-test and Pearson correlation were evaluated between the different methods. Degree of agreement between the calculated methods and direct method was detected by Bland–Altman graphical plots. Results: A strong correlation was found between all calculated LDL-C methods and direct low-density lipoprotein cholesterol method (D-LDL-C) assay, that is, F-LDL-C versus D-LDL-C = 0.94; A-LDL-C versus D-LDL-C = 0.93 and MF-LDL-C versus D-LDL-C = 0.95. No statistically significant difference was found between D-LDL-C and MF-LDL-C. Bland–Altman plot for MF-LDL-C showed minimal negative bias. Conclusions: The study pointed out that MF-LDL-C correlated maximally with D-LDL-C estimation at all levels of triglycerides and MF-LDL-C can be used in place of D-LDL-C when the direct method cannot be afforded. PMID:25949053

  20. Cholesterol Status Modulates mRNA and Protein Levels of Genes Associated with Cholesterol Metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary saturated (S), monounsaturated (MU) and polyunsaturated (PU) fatty acids (FA) and cholesterol have been shown to be major determinants of plasma lipoprotein profiles. The objective was to determine the effect of whole body cholesterol status and dietary fatty acid saturation on genes associ...

  1. Characterization of blood lipoproteins and validation of cholesterol and triacylglycerol assays for free-ranging polar bears (Ursus maritimus).

    PubMed

    Whiteman, John P; Frank, Nicholas; Greller, Katie A; Harlow, Henry J; Ben-David, Merav

    2013-05-01

    Blood triacylglycerol (TG) and lipoproteins are important variables for evaluating nutritional status of wildlife, but measurements are often expensive and difficult. Performance of a small, portable blood analyzer intended for human medical diagnostics was evaluated in measuring these variables in plasma and serum from free-ranging polar bears (Ursus maritimus), which are experiencing nutritional stress related to sea ice loss. The analyzer accurately tracked changes in concentration of total cholesterol (Ctotal), cholesterol associated with high-density lipoprotein (CHDL), and TG during a validation protocol of diluting samples and spiking them with exogenous cholesterol and glycerol. Values of Ctotal and TG agreed well with values obtained by other methods (ultracentrifugation followed by colorimetric assays); agreement was variable for values of cholesterol associated with specific lipoproteins. Similar to a study of captive polar bears, ultracentrifugation methods revealed greater TG in very low-density lipoproteins than in low-density lipoprotein, which is unusual and merits additional study. PMID:23632660

  2. Relation between high density lipoprotein cholesterol and coronary artery disease in asymptomatic men

    SciTech Connect

    Uhl, G.S.; Troxler, R.G.; Hickman, J.R. Jr.; Clark, D.

    1981-11-01

    The well established inverse relation of high density lipoprotein cholesterol (HDL) and the risk of coronary artery disease was tested in a cross-sectional group of 572 asymptomatic aircrew members who were being screened for risk of coronary artery disease. A battery of tests was performed, including determinations of fasting serum cholesterol, HDL cholesterol and triglycerides and performance of a maximal symptom-limited exercise tolerance test. Of the 572 patients, 132 also had an abnormal S-T segment response to exercise testing or were otherwise believed to have an increased risk of organic heart disease and subsequently underwent coronary angiography. Significant coronary artery disease was found in 16 men and minimal or subcritical coronary disease in 14; coronary angiograms were normal in the remaining 102 men. The remaining 440 men, who were believed to have a 1 percent chance of having coronary artery disease by sequential testing of risk factors and treadmill testing, had a mean cholesterol level of 213 mg/100 ml, a mean HDL cholesterol of 51 mg/100 ml and a mean cholesterol/HDL ratio of 4.4. The mean values of cholesterol, HDL cholesterol and cholesterol/HDL cholesterol did not differ significantly in men with normal angiographic finding and those with subcritical coronary disease. However, 14 of 16 men with coronary artery disease had a cholesterol/HDL ratio of 6.0 or more whereas only 4 men with normal coronary arteries had a ratio of 6.0 or more. Of the classical coronary risk factors evaluated, the cholesterol/HDL ratio of 6.0 or more had the highest odds ratio (172:1). It appears that determination of HDL cholesterol level helps to identify asymptomatic persons with a greater risk of having coronary artery disease.

  3. ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

    PubMed Central

    2014-01-01

    Background Dysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification. Methods In this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls. Results Gene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE. Conclusion Increased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis. PMID:25064003

  4. Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses.

    PubMed

    Li, Henry Y; Appelbaum, Frederick R; Willman, Cheryl L; Zager, Richard A; Banker, Deborah E

    2003-05-01

    The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance. PMID:12506040

  5. Serum reserve cholesterol binding capacity (SRCBC): the relative importance of different lipoprotein classes.

    PubMed

    Børresen, A L; Berg, K

    1981-01-01

    Findings by several authors have motivated studies in our laboratory on the relationship between HDL and "serum reserve cholesterol binding capacity" (SRCBC). We found that incubation for 25 hours at 37 degrees C provided optimal conditions for uptake and saturation when 14 mg sonicated and pulverized cholesterol was added to 1 ml serum. Upon separation of serum to which 14C labelled cholesterol had been added, into lipoprotein classes, a higher cpm:protein ratio than expected (from the free cholesterol:protein ratio, assuming isotope exchange exclusively) was found in LDL and the HDL fraction. In a second series of experiments, the different lipoprotein classes were separated prior to addition of 14C-cholesterol. The highest capacity for uptake of labelled cholesterol was found in the HDL fraction. The major part of the 14C-cholesterol appeared in the LDL density area when this HDL fraction was subjected to repeated ultracentrifugation. This suggested that the uptake of added cholesterol by HDL had led to the formation of an altered particle with density characteristics similar to those of LDL particles. This was confirmed by the demonstration of a "new" particle which contained apoA-I, apoA-II, and apoE, but no apoB or Lp(a) antigen. Its electrophoretic mobility was similar to that of HDL. Electron microscopy revealed that this particle is larger than normal HDL. The findings suggest that a sub-population of HDL molecules may be responsible for serum binding of added excess cholesterol. PMID:6794547

  6. Low-density lipoprotein cholesterol level and statin use among Medicare beneficiaries with diabetes mellitus.

    PubMed

    Qualls, Laura G; Hammill, Bradley G; Maciejewski, Matthew L; Curtis, Lesley H; Jones, W Schuyler

    2016-05-01

    At the time of this study, guidelines recommended a primary goal of low-density lipoprotein cholesterol level less than 100 mg/dL for all patients, an optional goal of low-density lipoprotein cholesterol less than 70 mg/dL for patients with overt cardiovascular disease and statins for patients with diabetes and overt cardiovascular disease and patients 40 years and older with diabetes and at least one risk factor for cardiovascular disease. This study examined statin use and achievement of lipid goals among 111,730 Medicare fee-for-service beneficiaries 65 years and older in 2011. Three-quarters of patients met the low-density lipoprotein cholesterol goal of less than 100 mg/dL. Patients with cardiovascular disease were more likely to meet the goal than those without, not controlling for other differences. Patients on a statin were more likely to meet the goal. There is considerable opportunity for improvement in cholesterol management in high-risk patients with diabetes mellitus. PMID:26802221

  7. High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells.

    PubMed

    Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-09-18

    Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt. PMID:26255968

  8. High-density-lipoprotein cholesterol and types of alcoholic beverages consumed among men and women.

    PubMed Central

    Parker, D R; McPhillips, J B; Derby, C A; Gans, K M; Lasater, T M; Carleton, R A

    1996-01-01

    OBJECTIVES. Differences by sex in the relationship between high-density-lipoprotein (HDL) cholesterol and consumption of alcoholic beverages were examined in 1516 individuals. METHODS. Questionnaires and blood-sample data from cross-sectional surveys were analyzed. RESULTS. Both beer and liquor were independently associated with increased HDL cholesterol in the total group, in men, and in women after covariates were controlled for. Wine was associated with a significant increase in HDL cholesterol in women only. CONCLUSIONS. Among women and men, amount may be more important than type of alcoholic beverage consumed. The independent effect of wine on HDL cholesterol among men remains unclear since few men in this population consumed wine exclusively or in large quantities. PMID:8669505

  9. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits.

    PubMed

    Badimon, J J; Badimon, L; Galvez, A; Dische, R; Fuster, V

    1989-03-01

    The effects of in vivo administration of high density lipoprotein-very high density lipoprotein (HDL-VHDL) on the development of aortic fatty streaks were studied in cholesterol-fed rabbits. The rabbits received a 0.5% cholesterol-rich diet for 8 weeks. During this period, the HDL-VHDL group was intravenously administered with 50 mg/week of homologous HDL-VHDL protein; the control group received normal saline (0.9% NaCl). HDL-VHDL fraction was obtained at density range 1.063 to 1.25 gm/ml by ultracentrifugation of normal rabbit plasma. Along the study, plasma lipid levels followed a similar profile in both groups. At the completion of the study, atherosclerotic-like lipid-rich lesions covered 37.9 +/- 6% (X +/- SEM) of the intimal aortic surface in the control group, and 14.9 +/- 2.1% in the treated group (p less than 0.001). The values of total and free cholesterol, esterified cholesterol, and phospholipids deposited within vessel wall were significantly lower in the aortas of the HDL-VHDL treated group than those in the control group. Cholesterol accumulation in the livers was also significantly lower (p less than 0.01) in the treated group than in the control. We concluded that administration of homologous HDL-VHDL lipoprotein fraction to cholesterol-fed rabbits, dramatically inhibited the extent of aortic fatty streaks and lowered lipid deposition in the arterial wall and liver without modification of the plasma lipid levels. PMID:2927083

  10. Effect of cigarette smoke and dietary cholesterol on plasma lipoprotein composition

    SciTech Connect

    Hojnacki, J.L.; Mulligan, J.J.; Cluette, J.E.; Kew, R.R.; Stack, D.J.; Huber, G.L.

    1981-01-01

    Pigeons were assigned to four treatment groups: 1) Controls fed a chow diet ad libitum and retained in their cages; 2) Sham pigeons fed a cholesterol-saturated fat diet and exposed to fresh air by the Lorillard smoking machine; 3) Low nicotine-low carbon monoxide (LoLo) animals also fed the cholesterol diet and exposed to low concentrations of cigarette smoke; and 4) High nicotine-high carbon monoxide (HiHi) birds fed the cholesterol diet and subjected to high concentrations of inhalants. Plasma very low density (VLDL), low density (LDL), and high density (HDL) lipoproteins were isolated by density gradient ultracentrifugation. Smoke-related differences appeared in HiHi HDL which contained relatively more free and esterified cholesterol and total lipid, but less total protein than HDL from Sham-smoked pigeons. VLDL from birds exposed to cigarette smoke (LoLo and HiHi) contained relatively more total lipid, but less total protein than VLDL from Sham pigeons. Inhalation smoke produced a marked depression in the HDL2/HDL3 ratio resulting from an increased proportion of the HDL3 subfraction relative to HDL2. Pigeons fed the cholesterol-saturated fat diet circulated HDL with greater free and esterified cholesterol mass than Controls. Diet also altered the type of cholesteryl ester present in HDL with cholesteryl linoleate representing the predominant form in Control pigeons and cholesteryl oleate in cholesterol-fed birds. These results demonstrate that cigarette smoking can mediate alterations in lipoprotein composition independent of changes induced by dietary cholesterol and saturated fat.

  11. Effect of a diet high in monounsaturated fat from almonds on plasma cholesterol and lipoproteins.

    PubMed

    Spiller, G A; Jenkins, D J; Cragen, L N; Gates, J E; Bosello, O; Berra, K; Rudd, C; Stevenson, M; Superko, R

    1992-04-01

    The effect of almonds as part of a low saturated fat, low cholesterol, high-fiber diet was studied in 26 adults (13 men, 13 women). The baseline diet was modified in a similar way for all subjects by limiting meat, fatty fish, high-fat milk products, eggs, and saturated fat. Grains, beans, vegetables, fruit, and low-fat milk products were the foundation of the diet. During the almond diet period, raw almonds (100 mg/day) supplied 34 g/day of monounsaturated fatty acid (MUFA), 12 g/day of polyunsaturated fatty acid, and 6 g/day of saturated fatty acid. Almond oil was the only oil allowed for food preparation. There was a rapid and sustained reduction in low-density lipoprotein cholesterol without changes in high-density lipoprotein cholesterol. This was reflected in a total plasma cholesterol decrease from (means +/- SEM) 235 +/- 5.0 at baseline to 215 +/- 5.0 at 3 weeks, and to 214 +/- 5.0 mg/dl at 9 weeks (p less than 0.001). When the consumption of nuts high in MUFA increases the fat content of the diet, reduction rather than elevation of plasma cholesterol has to be expected, possibly due to the MUFA content of these nuts. PMID:1315812

  12. [Cholesterol bound to high density lipoproteins: critical review of the methods of analysis and personal data].

    PubMed

    Orso Giacone, G

    1982-01-01

    It is widely known that atherosclerosis through its complication, i.e. heart and brain infarction, is at the present the main cause of death. The atherosclerotic process has been shown in correlation with hyperlipemia especially as far as the plasma lipoprotein cholesterol level is concerned. A preminent role in removing cholesterol from tissues and arterial walls then in preventing atherosclerosis is played by a specific class of plasma lipoproteins, the high density lipoproteins (HDL). Since the HDL-colesterol level seems to have an inverse correlation with the atherosclerotic disease it is of primary importance to define a reliable and reproducible technique to measure it. One of the aims of this paper was to examine the different methods now available for such a determination. This analysis has underlined the discrepancy among the reference values reported in the literature. However, all the authors agree that only the simultaneous measurement of total and HDL-colesterol levels is of prognostic value. Personal studies are here reported on the relationship between total and HDL-colesterol levels and risk factor of cardiovascular diseases. The two mentioned laboratory analyses have been performed on blood samples from 250 between male and female human subjects of different age. The obtained results show that the highest HDL-colesterol concentrations determined by a lipoprotein precipitation procedure with dextran sulphate, are typical in the first ten years of life both in male and in female, while the lowest levels of plasma HDL-cholesterol have been evintiated during the fifth decade of life, when the total cholesterol and the risk of cardiovascular complications rich the highest values. In a following set of investigations, the already examined blood parameters together with the risk factor values have been examined in two groups of subjects, the first one represented by adult healthy persons the second one by patients of similar age from a cardiovascular

  13. Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease.

    PubMed

    Marzolo, Maria-Paz; Bu, Guojun

    2009-04-01

    Amyloid-beta (Abeta) peptide accumulation in the brain is central to the pathogenesis of Alzheimer's disease (AD). Abeta is produced through proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apoER2, interact with APP and regulate its endocytic trafficking. Additionally, APP trafficking and processing are greatly affected by cellular cholesterol content. In this review, we summarize the current understanding of the roles of lipoprotein receptors and cholesterol in APP trafficking and processing and their implication for AD pathogenesis and therapy. PMID:19041409

  14. Genomic Determinants of Triglyceride and Cholesterol Distribution into Lipoprotein Fractions in the Rat

    PubMed Central

    Hodúlová, Miloslava; Šedová, Lucie; Křenová, Drahomíra; Liška, František; Krupková, Michaela; Kazdová, Ludmila; Tremblay, Johanne; Hamet, Pavel; Křen, Vladimír; Šeda, Ondřej

    2014-01-01

    The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8–13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred

  15. Current guidelines for high-density lipoprotein cholesterol in therapy and future directions

    PubMed Central

    Subedi, Bishnu H; Joshi, Parag H; Jones, Steven R; Martin, Seth S; Blaha, Michael J; Michos, Erin D

    2014-01-01

    Many studies have suggested that a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) is low high-density lipoprotein cholesterol (HDL-C). Therefore, increasing HDL-C with therapeutic agents has been considered an attractive strategy. In the prestatin era, fibrates and niacin monotherapy, which cause modest increases in HDL-C, reduced ASCVD events. Since their introduction, statins have become the cornerstone of lipoprotein therapy, the benefits of which are primarily attributed to decrease in low-density lipoprotein cholesterol. Findings from several randomized trials involving niacin or cholesteryl ester transfer protein inhibitors have challenged the concept that a quantitative elevation of plasma HDL-C will uniformly translate into ASCVD benefits. Consequently, the HDL, or more correctly, HDL-C hypothesis has become more controversial. There are no clear guidelines thus far for targeting HDL-C or HDL due to lack of solid outcomes data for HDL specific therapies. HDL-C levels are only one marker of HDL out of its several structural or functional properties. Novel approaches are ongoing in developing and assessing agents that closely mimic the structure of natural HDL or replicate its various functions, for example, reverse cholesterol transport, vasodilation, anti-inflammation, or inhibition of platelet aggregation. Potential new approaches like HDL infusions, delipidated HDL, liver X receptor agonists, Apo A-I upregulators, Apo A mimetics, and gene therapy are in early phase trials. This review will outline current therapies and describe future directions for HDL therapeutics. PMID:24748800

  16. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) t...

  17. A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

    PubMed Central

    Loregger, Anke; Cook, Emma Claire Laura; Nelson, Jessica Kristin; Moeton, Martina; Sharpe, Laura Jane; Engberg, Susanna; Karimova, Madina; Lambert, Gilles; Brown, Andrew John

    2015-01-01

    Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake. PMID:26527619

  18. Low-density lipoprotein cholesterol versus particle number in middle school children

    PubMed Central

    Mietus-Snyder, Michele; Drews, Kimberly L.; Otvos, James D.; Willi, Steven M.; Foster, Gary D.; Jago, Russell; Buse, John B.

    2013-01-01

    Objectives To characterize lipids and lipoproteins in a diverse school-based cohort and identify features associated with discordance between low-density lipoprotein cholesterol (LDL-C) and LDL particle (LDL-P). Study design Sixth grade children enrolled in the HEALTHY trial (n=2,384; mean age 11.3 ± 0.6 yr; 54.2% female) were evaluated for standard lipids, lipoprotein particles measured by nuclear magnetic resonance, and homeostatic model of insulin resistance (HOMA-IR). Characteristics of subgroups with values of LDL-C and LDL-P discordant by >20 percentile units, an amount reasoned to be clinically significant, were compared. Results Four hundred twenty-eight (18%) of children were in the LDL-P < LDL-C subgroup and 375 (16%) in the LDL-P > LDL-C subgroup. Those with LDL-P > LDL-C had significantly higher BMI, waist circumference, HOMA-IR, triglycerides, systolic and diastolic blood pressure, and reflected a greater Hispanic ethnic composition but fewer of black race than both the concordant (LDL-P ≅ LDL-C) and opposite discordant (LDL-P < LDL-C) subgroups. Conclusions There is as much lipoprotein cholesterol compositional heterogeneity in 6th graders as has been described in adults and a discordant atherogenic phenotype of LDL-P > LDL-C, common in obesity, is often missed when only LDL-C is considered. Conversely, many children with moderate-risk cholesterol measures (75th to 99th percentile) have a lower LDL particle burden. PMID:23415622

  19. Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

  20. Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol.

    PubMed

    Vega, G L; von Bergmann, K; Grundy, S M; Blumenschein, S; Carter, N B; Laeis, P; Lindenthal, B; von Bergmann, J; Simatupang, A; Lutjohann, D; Adams-Huet, B

    1999-07-01

    Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL

  1. The amount of dietary cholesterol changes the mode of effects of (n-3) polyunsaturated fatty acid on lipoprotein cholesterol in hamsters.

    PubMed

    Lin, Mei-Huei; Lu, Shao-Chun; Huang, Po-Chao; Liu, Young-Chau; Liu, Shyun-Yeu

    2004-01-01

    This study was designed to investigate the effects of the interaction between dietary (n-3) polyunsaturated fatty acids (PUFA) and different dietary cholesterol content on plasma and liver cholesterol in hamsters. Male Syrian hamsters consumed diets containing an incremental increase in dietary cholesterol content (0, 0.025, 0.05, 0.1 and 0.2%, w/w) with either (n-3) PUFA (21 g/100 g fatty acids) or (n-6) PUFA (37.4 g/100 g fatty acids) fat for 6 weeks. In hamsters fed the nonatherogenic diet (0 or 0.025% dietary cholesterol), very low density lipoprotein (VLDL)-cholesterol levels in the (n-3) PUFA group were not significantly different from those in the (n-6) PUFA group, and low density lipoprotein (LDL)-cholesterol levels in the (n-3) PUFA group were significantly lower than those in the (n-6) PUFA group. In contrast, in hamsters fed the atherogenic diet (0.1 or 0.2% dietary cholesterol), VLDL- and LDL-cholesterol levels in the (n-3) PUFA group were significantly higher than those in the (n-6) PUFA group, in a dose-dependent manner. When the hamsters were fed with 0, 0.025, 0.05, 0.1 or 0.2% (w/w) dietary cholesterol, high density lipoprotein (HDL) cholesterol concentration was significantly lower in the (n-3) PUFA group than those in the (n-6) PUFA group. Hepatic cholesteryl esters were significantly lower, while hepatic microsomal acyl-coenzyme A:cholesterol acyltransferase activity and VLDL-cholesteryl esters were significantly higher in hamsters fed (n-3) PUFA with the atherogenic diet (0.1 or 0.2% dietary cholesterol) than in those fed (n-6) PUFA with the atherogenic diet. Our results demonstrate that the amount of dietary cholesterol is an important factor in determining the mode and extent of effects of dietary (n-3) PUFA, especially on VLDL- and LDL-cholesterol levels. When dietary cholesterol intake was above 0.1% (w/w), the plasma cholesterol-lowering effect of (n-3) PUFA disappeared, and instead, it showed a cholesterol-increasing effect. However, the

  2. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.

    PubMed

    Ness, G C; Zhao, Z; Lopez, D

    1996-01-15

    Inhibitors of cholesterol biosynthesis are believed to lower serum cholesterol levels by enhancing the removal of serum low-density lipoprotein (LDL) by increasing hepatic LDL receptor function. Thus, the effects of several different inhibitors of cholesterol biosynthesis were examined for their effects on the expression of the hepatic LDL receptor in rats. We found that administration of inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase such as lovastatin, pravastatin, fluvastatin, and rivastatin resulted in increased hepatic LDL receptor mRNA levels. Surprisingly, these agents failed to increase levels of immunoreactive LDL receptor protein in rat liver even when the dose and length of treatment were increased. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, caused even greater increases in hepatic LDL receptor mRNA levels, but did not increase levels of immunoreactive protein. Further investigation revealed that the rate of degradation of the hepatic LDL receptor was increased in rats given inhibitors of cholesterol biosynthesis. The greatest increase in the rate of degradation was seen in animals treated with zaragozic acid A which caused the largest increase in hepatic LDL receptor mRNA levels. In contrast, hepatic LDL receptor protein was stabilized in cholesterol-fed rats. It appears that increased potential for LDL receptor protein synthesis, reflected in increased mRNA levels, is offset by a corresponding increase in the rate of receptor protein degradation resulting in constant steady-state levels of hepatic LDL receptor protein. These findings are suggestive of increased cycling of the hepatic LDL receptor. This postulated mechanism can provide for enhanced hepatic uptake of lipoproteins without increasing steady-state levels of LDL receptor protein. PMID:8561503

  3. Down-regulation of lipoprotein lipase increases ABCA1-mediated cholesterol efflux in THP-1 macrophages.

    PubMed

    Kawashima, Ryoko L; Medh, Jheem D

    2014-08-01

    The ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of excess cholesterol from foam cells to lipid-poor apolipoprotein A-I, in a process called reverse cholesterol transport. Lipoprotein lipase (LPL) is a lipolytic enzyme expressed by macrophages within atherosclerotic lesions. Lentivirus-mediated RNA interference was used to genetically knock-down (KD) the expression of LPL in THP-1 macrophages. Silencing of the LPL gene was confirmed by end-point PCR, real time PCR, and protein analysis. Suppression of LPL expression correlated with a 1.6-fold up-regulation of ABCA1 mRNA levels, and resulted in a 4.5-fold increase in ABCA1-dependent cholesterol efflux. Replenishing LPL by addition of purified bovine LPL to the cell culture media resulted in down-regulation of ABCA1-mediated cholesterol efflux in both wild-type and LPL knockdown cells. These findings suggest an inverse correlation between macrophage LPL levels and ABCA1 cholesterol transport activity. PMID:25017912

  4. [Correlations of lipoprotein metabolism indicators in persons with low and high cholesterol ester transport activity].

    PubMed

    Tvorogova, M G; Rozhkova, T A; Kukharchuk, V V; Titov, V N

    1999-01-01

    For clarifying the role of plasma cholesterol ester transfer activity (CETA) in forming hyperlipoproteinemia (HLP) and determination of high density lipoproteins cholesterol (Ch HDL) level, lipoprotein metabolism indicators were compared for individuals with high and low CETA. 257 subjects were investigated: 195 patients with different forms of hereditary HLP and individuals without HLP: 34 healthy and 28 with coronary heart disease (CHD). Lipids were determined enzymatically, apoproteins content by immunoturbodimetric and immunodiffusion methods. CETA and cholesterol esterification rate (CER) were measured through autological methods. Selected groups of patients with high and low CETA were significantly distinguished only by plasma Ch level (average Ch > 6.2 mmol/l in both groups), free Ch HDL and CER. The groups were not significantly different by men-women ratio (chi 2 = 0.016, p = 0.9) and CHD patients share (chi 2 = 0.126, p = 0.723). The correlation between CETA and Ch levels was significant for healthy individuals only. The data does not correspond to assumption of exclusively atherogenic influence of high CETA: 1) no correlation between CETA and atherogenic parameters of LP metabolism among different HLP forms was found; 2) Ch HDL levels were not distinguished at high and low CETA; 3) no domination of CHD patients among the subjects with high CETA was found. PMID:10547884

  5. High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity

    PubMed Central

    Rohatgi, Anand

    2015-01-01

    A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies. PMID:25968932

  6. High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity.

    PubMed

    Rohatgi, Anand

    2015-01-01

    A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies. PMID:25968932

  7. 21-Methylpyrenyl-cholesterol stably and specifically associates with lipoprotein peripheral hemi-membrane: A new labelling tool

    SciTech Connect

    Gaibelet, Gérald; Tercé, François; Bertrand-Michel, Justine; Allart, Sophie; Azalbert, Vincent; Lecompte, Marie-France; Collet, Xavier; Orlowski, Stéphane

    2013-11-01

    Highlights: •21-Methylpyrenyl-cholesterol specifically and stably associates to lipoproteins. •It is not esterified by LCAT, and thus reliably labels their peripheral hemi-membrane. •HDL vs. LDL are well distinguishable by various fluorescent labelling characteristics. •LDL peripheral hemi-membrane harbors cholesterol-rich ordered lipid (micro)domains. •Cultured cells can be stained by such labelled lipoproteins-mediated delivery. -- Abstract: Lipoproteins are important biological components. However, they have few convenient fluorescent labelling probes currently reported, and their physiological reliability can be questioned. We compared the association of two fluorescent cholesterol derivatives, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), to serum lipoproteins and to purified HDL and LDL. Both lipoproteins could be stably labelled by Pyr-met-Chol, but virtually not by NBD-Chol. At variance with NBD-Chol, LCAT did not esterify Pyr-met-Chol. The labelling characteristics of lipoproteins by Pyr-met-Chol were well distinguishable between HDL and LDL, regarding dializability, associated probe amount and labelling kinetics. We took benefit of the pyrene labelling to approach the structural organization of LDL peripheral hemi-membrane, since Pyr-met-Chol-labelled LDL, but not HDL, presented a fluorescence emission of pyrene excimers, indicating that the probe was present in an ordered lipid micro-environment. Since the peripheral membrane of LDL contains more sphingomyelin (SM) than HDL, this excimer formation was consistent with the existence of cholesterol- and SM-enriched lipid microdomains in LDL, as already suggested in model membranes of similar composition and reminiscent to the well-described “lipid rafts” in bilayer membranes. Finally, we showed that Pyr-met-Chol could stain cultured PC-3 cells via lipoprotein-mediated delivery, with a staining pattern well different to that observed with NBD

  8. Low density lipoprotein bionanoparticles: From cholesterol transport to delivery of anti-cancer drugs

    PubMed Central

    Harisa, Gamaleldin I.; Alanazi, Fars K.

    2013-01-01

    In this review article, we highlight the importance of low-density lipoprotein (LDL) and its implications in the field of drug delivery to cancer cells. LDL is naturally occurring bionanoparticles (BNP) with a size of 18–25 nm. These BNPs specifically transport cholesterol to cells expressing the LDL receptors (LDLRs). Several tumors overexpress LDLRs, presumably to provide cholesterol for sustaining a high rate of membrane synthesis. LDL BNPs are biocompatible and biodegradable, favorably bind hydrophobic and amphiphilic drugs, are taken up by a receptor-mediated mechanism, have a half-life of 2–4 days, and can be rerouted. Drugs can be loaded onto LDL BNPs by surface loading, core loading, and apoprotein interaction. LDL may be used as a drug carrier for treatment of atherosclerosis, cancer, and in photodynamic therapies. PMID:25561862

  9. Human apolipoprotein E allele and docosahexaenoic acid intake modulate peripheral cholesterol homeostasis in mice.

    PubMed

    Pinçon, Anthony; Coulombe, Jean-Denis; Chouinard-Watkins, Raphaël; Plourde, Mélanie

    2016-08-01

    Carrying at least one apolipoprotein E ε4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6ω3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low-density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake. PMID:27239755

  10. Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters.

    PubMed

    Kothari, H V; Poirier, K J; Lee, W H; Satoh, Y

    1997-01-01

    As a result of screening, several isoflavans were identified to be antagonists of cholesterol ester transfer protein (CETP) activity. The present study evaluates CGS 25159, a synthetic isoflavan, as a putative inhibitor of CETP activity of human and hamster plasma. Determined by [3]CE transfer from HDL to VLDL + LDL fraction or by fluorescent-CE transfer assay, CGS 25159 inhibited CETP in both human plasma bottom fraction (d = 1.21 g/ml) and in plasma from Golden Syrian Hamsters with an IC50 < 10 microM. The compound also inhibited (IC 50 approximately equal to 15 microM) the reciprocal transfer of triglycerides in the incubated whole plasma from normal and hyperlipidemic hamsters. When orally administered to normolipidemic hamsters, CGS 25159 (10 mg/kg, 4 days) reduced plasma transfer activity by 35-60%. Treatment with CGS 25159 (10 and 30 mg/kg, p.o.) resulted in dose dependent and time dependent changes in CETP activity. After two weeks of treatment at 10 mg/kg, the changes in VLDL + LDL cholesterol, total triglycerides and HDL cholesterol were -22 +/- 4.6*, -23 +/- 7.5 and +10 +/- 2.8%, respectively. The corresponding changes at 30 mg/kg were -28 +/- 5.5*, -38 +/- 6.8* and +29 +/-4.4.*%, (*, P, 0.05; mean +/- S.E.M., n = 6). A single spin gradient density ultracentrifugation of plasma lipoproteins and treated animals showed an increase in HDL cholesterol and a redistribution to larger HDL particles. These data support the contention that pharmacological down regulation of CETP activity could result in favorable changes in lipoprotein profile. PMID:9051198

  11. Lack of Association between High-Density Lipoprotein Cholesterol and Angiographic Coronary Lesion Severity in Chinese Patients with Low Background Low-Density Lipoprotein Cholesterol

    PubMed Central

    Su, Chieh-Shou; Chen, Kuan-Ju; Sheu, Wayne Huey-Herng; Yang, Ya-Ling; Liu, Tsun-Jui; Chang, Wei-Chun; Wang, Kuo-Yang; Lee, Wen-Lieng

    2015-01-01

    Background The atheroprotective role of high-density lipoprotein (HDL-C) particles as measured by HDL-C level in coronary arterial disease (CAD) remains unsettled. The aim of our study was to ascertain whether HDL-C was associated with the development and severity of coronary artery disease in Chinese patients who underwent coronary angiogram with low background Low-density lipoprotein (LDL-C) levels, which has not been previously investigated. Methods Between March 1995 and May 2000, 566 consecutive patients (408 males, 66.7 ± 11.3 years of age) with background LDL-C less than 100 mg/dl who underwent coronary artery angiography at our cath lab for suspected CAD were retrospectively recruited into the study. The severity of coronary lesions was measured by conventional coronary angiography and modified Gensini scores. Results In those subjects with significant coronary lesions, there were more males and conventional CAD risk factors of diabetes mellitus, smoking, and chronic renal disease. They were also older compared to those in the control group. However, total cholesterol, LDL-C, HDL-C, triglyceride levels and use of statins were similar in both groups. In those subjects with significant coronary lesions, there was no difference in conventional coronary lesion severity or modified Gensini score between the quartered HDL-C subgroups. Furthermore, there was no significant correlation between serum HDL-C level and modified Gensini scores. In linear regression analysis, HDL-C was not an independent predictor for modified Gensini scores. Furthermore, HDL-C was also not an independent risk factor for the presence of significant coronary lesions in low LDL-C patients in logistic regression analysis. Conclusions In Chinese patients with low background LDL-C, serum HDL-C was not associated with development of CAD or lesion severity in patients with suspected CAD. Therefore, HDL-C did not appear to be atheroprotective in these patients. PMID:27122918

  12. Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol.

    PubMed

    Della Badia, Laura A; Elshourbagy, Nabil A; Mousa, Shaker A

    2016-08-01

    Statins and other lipid-lowering drugs have dominated the market for many years for achievement of recommended levels of low-density lipoprotein cholesterol (LDL-C). However, a substantial number of high-risk patients are unable to achieve the LDL-C goal. Proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a new, promising key therapeutic target for hypercholesterolemia. PCSK9 is a protease involved in chaperoning the low-density lipoprotein receptor to the process of degradation. PCSK9 inhibitors and statins effectively lower LDL-C. The PCSK9 inhibitors decrease the degradation of the LDL receptors, whereas statins mainly interfere with the synthetic machinery of cholesterol by inhibiting the key rate limiting enzyme, the HMG CoA reductase. PCSK9 inhibitors are currently being developed as monoclonal antibodies for their primary use in lowering LDL-C. They may be especially useful for patients with homozygous familial hypercholesterolemia, who at present receive minimal benefit from traditional statin therapy. The monoclonal antibody PCSK9 inhibitors, recently granted FDA approval, show the most promising safety and efficacy profile compared to other, newer LDL-C lowering therapies. This review will primarily focus on the safety and efficacy of monoclonal antibody PCSK9 inhibitors in comparison to statins. The review will also address new, alternative PCSK9 targeting drug classes such as small molecules, gene silencing agents, apolipoprotein B antisense oligonucleotides, and microsomal triglyceride transfer protein inhibitors. PMID:27133571

  13. Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus

    PubMed Central

    Bays, Harold E

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-altering drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy. PMID:25045281

  14. Guar gum effects on plasma low-density lipoprotein and hepatic cholesterol metabolism in guinea pigs fed low- and high-cholesterol diets: a dose-response study.

    PubMed

    Fernandez, M L; Sun, D M; Tosca, M; McNamara, D J

    1995-01-01

    Guinea pigs were fed semipurified diets containing either 0% or 12.5% guar gum (GG) with 0.04% cholesterol or increasing concentrations of GG (0%, 2.5%, 5%, 7.5%, 10%, and 12.5%) with 0.25% cholesterol (by wt). Compared to the 0% GG diet with 0.04% cholesterol, intake of the 12.5% GG diet with 0.04% cholesterol lowered plasma low-density-lipoprotein (LDL) concentrations, the ratio of LDL cholesteryl ester to protein, hepatic cholesterol concentrations, and the activity of acyl-CoA:cholesterol acyltransferase (ACAT), and increased 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and hepatic apo B/E receptor number (P < 0.01). Intake of GG by animals fed 0.25% cholesterol diets resulted in modest effects on hepatic cholesterol pools and plasma LDL concentrations; however, significant negative correlations were found between both plasma LDL cholesterol and hepatic free cholesterol concentrations with the amount of dietary GG (P < 0.05). Hepatic HMG-CoA reductase was suppressed by the 0.25% cholesterol intake, and GG did not reverse this suppression. In contrast, ACAT activity was negatively correlated with the amount of dietary GG (P < 0.05), and GG intake increased the number of hepatic apo B/E receptors at all intakes with the 0.25% cholesterol diets. These results demonstrate that intake of GG significantly alters endogenous cholesterol metabolism by decreasing hepatic cholesterol pools, altering hepatic cholesterol homeostasis, and reducing plasma LDL concentrations. PMID:7825524

  15. Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease.

    PubMed

    Zhang, Linqiang; Zhang, Zhiguo; Li, Yunhai; Liao, Shasha; Wu, Xiaoyun; Chang, Qing; Liang, Bin

    2015-01-01

    Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD. PMID:26522240

  16. Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

    PubMed Central

    Xie, Ping; Zhu, Hongling; Jia, Lin; Ma, Yinyan; Tang, Weiqing; Wang, Youlin; Xue, Bingzhong; Shi, Hang; Yu, Liqing

    2014-01-01

    Objective The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. Methods and results We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses human NPC1L1 in gastrointestinal tract only (DKO/L1IntOnly mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that human NPC1L1 was localized at the intestinal brush border membrane of DKO/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1IntOnly mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1IntOnly mice. Conclusion Our findings from DKO/L1IntOnly mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice. PMID:25463095

  17. 21-Methylpyrenyl-cholesterol stably and specifically associates with lipoprotein peripheral hemi-membrane: a new labelling tool.

    PubMed

    Gaibelet, Gérald; Tercé, François; Bertrand-Michel, Justine; Allart, Sophie; Azalbert, Vincent; Lecompte, Marie-France; Collet, Xavier; Orlowski, Stéphane

    2013-11-01

    Lipoproteins are important biological components. However, they have few convenient fluorescent labelling probes currently reported, and their physiological reliability can be questioned. We compared the association of two fluorescent cholesterol derivatives, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), to serum lipoproteins and to purified HDL and LDL. Both lipoproteins could be stably labelled by Pyr-met-Chol, but virtually not by NBD-Chol. At variance with NBD-Chol, LCAT did not esterify Pyr-met-Chol. The labelling characteristics of lipoproteins by Pyr-met-Chol were well distinguishable between HDL and LDL, regarding dializability, associated probe amount and labelling kinetics. We took benefit of the pyrene labelling to approach the structural organization of LDL peripheral hemi-membrane, since Pyr-met-Chol-labelled LDL, but not HDL, presented a fluorescence emission of pyrene excimers, indicating that the probe was present in an ordered lipid micro-environment. Since the peripheral membrane of LDL contains more sphingomyelin (SM) than HDL, this excimer formation was consistent with the existence of cholesterol- and SM-enriched lipid microdomains in LDL, as already suggested in model membranes of similar composition and reminiscent to the well-described "lipid rafts" in bilayer membranes. Finally, we showed that Pyr-met-Chol could stain cultured PC-3 cells via lipoprotein-mediated delivery, with a staining pattern well different to that observed with NBD-Chol non-specifically delivered to the cells. PMID:24103760

  18. Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size[S

    PubMed Central

    van Schalkwijk, Daniël B.; de Graaf, Albert A.; van Ommen, Ben; van Bochove, Kees; Rensen, Patrick C. N.; Havekes, Louis M.; van de Pas, Niek C. A.; Hoefsloot, Huub C. J.; van der Greef, Jan; Freidig, Andreas P.

    2009-01-01

    Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given. PMID:19515990

  19. Mechanism of the hepatic lipase induced accumulation of high-density lipoprotein cholesterol by cells in culture

    SciTech Connect

    Bamberger, M.; Lund-Katz, S.; Phillips, M.C.; Rothblat, G.H.

    1985-07-02

    Hepatic lipase can enhance the delivery of high-density lipoprotein (HDL) cholesterol to cells by a process which does not involve apoprotein catabolism. The incorporation of HDL-free (unesterified) cholesterol, phospholipid, and cholesteryl ester by cells has been compared to establish the mechanism of this delivery process. Human HDL was reconstituted with /sup 3/H-free cholesterol and (/sup 14/C)sphingomyelin, treated with hepatic lipase in the presence of albumin to remove the products of lipolysis, reisolated, and then incubated with cultured rat hepatoma cells. Relative to control HDL, modification of HDL with hepatic lipase stimulated both the amount of HDL-free cholesterol taken up by the cell and the esterification of HDL-free cholesterol but did not affect the delivery of sphingomyelin. Experiments utilizing HDL reconstituted with /sup 14/C-free cholesterol and (/sup 3/H)cholesteryl oleoyl ether suggest that hepatic lipase enhances the incorporation of HDL-esterified cholesterol. However, the amount of free cholesterol delivered as a result of treatment with hepatic lipase was 4-fold that of esterified cholesterol. On the basis of HDL composition, the cellular incorporation of free cholesterol was about 10 times that which would occur by the uptake and degradation of intact particles. The preferential incorporation of HDL-free cholesterol did not require the presence of lysophosphatidylcholine. To correlate the events observed at the cellular level with alterations in lipoprotein structure, high-resolution, proton-decoupled /sup 13/C nuclear magnetic resonance spectroscopy (90.55 MHz) was performed on HDL3 in which the cholesterol molecules were replaced with (4-/sup 13/C)cholesterol by particle reconstitution.

  20. Hepatitis C Virus, Cholesterol and Lipoproteins — Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

    PubMed Central

    Felmlee, Daniel J.; Hafirassou, Mohamed Lamine; Lefevre, Mathieu; Baumert, Thomas F.; Schuster, Catherine

    2013-01-01

    Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects. PMID:23698400

  1. Influence of different molecular species of phosphatidylcholine on cholesterol transport from lipoprotein recombinants in the rat

    SciTech Connect

    Leduc, R.; Patton, G.M.; Atkinson, D.; Robins, S.J.

    1987-06-05

    Studies were performed to determine to what extent phosphatidylcholines (PCs) of different composition influence the turnover of lipoprotein cholesterol. Lipoprotein recombinants with the composition and structure of spherical high density lipoproteins (HDL-R) were prepared with apoproteins, /sup 14/C-labeled unesterified cholesterol (UC), a (3H)cholesteryl ester (CE), and one of four single molecular species of PC. PCs were selected to include relatively hydrophilic species (16:1-16:1 and 16:0-18:2 PCs) and relatively hydrophobic species (18:0-18:2 and 20:1-20:1 PCs). PCs were also selected to include molecules with novel acyl group pairs (16:1-16:1 and 20:1-20:1 PCs) that would permit the whole molecule to be traced during its clearance from the serum. Rats were injected with HDL-R as an intravenous bolus, and serum, liver, and bile samples were obtained for up to 2 h. The clearance from the serum of each PC was monoexponential with the two most hydrophilic species much more rapidly cleared than either of the two less hydrophilic species. Clearance of specific PCs was not accompanied by PC remodeling (i.e. transacylations), and in the main could not be attributed to the action of lecithin-cholesterol acyltransferase (LCAT). In incubations designed to simulate in vivo conditions, no more than 15% of the disappearance of 16:1-16:1 PC, one of the most rapidly cleared PCs, was due to the action of LCAT. With 20:1-20:1 PC, one of the least rapidly cleared PCs, no LCAT activity could be detected. The clearance of radiolabeled UC was multiexponential and closely corresponded to the rate of disappearance of each PC. The clearance of radiolabeled CE was linear and, in contrast to UC, was the same with the administration of different PCs. Uptake of radiolabeled UC by the liver and excretion of radiolabeled UC into bile took place in parallel and corresponded to the rapidity of turnover of UC (and PCs) in the serum.

  2. Body Fatness and Risk for Elevated Blood Pressure, Total Cholesterol, and Serum Lipoprotein Ratios in Children and Adolescents.

    ERIC Educational Resources Information Center

    Williams, Daniel P.; And Others

    1992-01-01

    Examines the relationship between body fat percent and risk for elevated blood pressure, serum total cholesterol, and serum lipoprotein ratios in 1,230 African-American and 2,090 white 5-18 year olds (1,667 males and 1,653 females). Results support body fatness standards in children and adolescents as cardiovascular risk factors. (SLD)

  3. High systemic levels of low-density lipoprotein cholesterol: fuel to the flames in inflammatory osteoarthritis?

    PubMed

    de Munter, Wouter; van der Kraan, Peter M; van den Berg, Wim B; van Lent, Peter L E M

    2016-01-01

    There is increasing evidence that low-density lipoprotein (LDL) cholesterol plays a role in the pathology of OA. Specifically, oxidized LDL (oxLDL), which has been shown to play an essential role during development of atherosclerosis, could be involved in processes such as synovial inflammation, cartilage destruction and bone deformations. OxLDL can activate synovial cells such as macrophages, endothelial cells and synovial fibroblasts, resulting in release of growth factors, MMP and pro-inflammatory cytokines. In this review article, we discuss the role of LDL and oxLDL in OA joint pathology and share our viewpoint of possible mechanisms by which these proteins could influence the development and progression of OA. The proposed theory could provide insight into the aetiopathology of OA and give rise to new potential treatments. PMID:26231344

  4. Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma.

    PubMed

    Simonelli, Sara; Gianazza, Elisabetta; Mombelli, Giuliana; Bondioli, Alighiero; Ferraro, Giovanni; Penco, Silvana; Sirtori, Cesare R; Franceschini, Guido; Calabresi, Laura

    2012-01-23

    An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case. PMID:22271127

  5. Cholesterol modulates Orai1 channel function.

    PubMed

    Derler, Isabella; Jardin, Isaac; Stathopulos, Peter B; Muik, Martin; Fahrner, Marc; Zayats, Vasilina; Pandey, Saurabh K; Poteser, Michael; Lackner, Barbara; Absolonova, Marketa; Schindl, Rainer; Groschner, Klaus; Ettrich, Rüdiger; Ikura, Mitsu; Romanin, Christoph

    2016-01-26

    STIM1 (stromal interaction molecule 1) and Orai proteins are the essential components of Ca(2+) release-activated Ca(2+) (CRAC) channels. We focused on the role of cholesterol in the regulation of STIM1-mediated Orai1 currents. Chemically induced cholesterol depletion enhanced store-operated Ca(2+) entry (SOCE) and Orai1 currents. Furthermore, cholesterol depletion in mucosal-type mast cells augmented endogenous CRAC currents, which were associated with increased degranulation, a process that requires calcium influx. Single point mutations in the Orai1 amino terminus that would be expected to abolish cholesterol binding enhanced SOCE to a similar extent as did cholesterol depletion. The increase in Orai1 activity in cells expressing these cholesterol-binding-deficient mutants occurred without affecting the amount in the plasma membrane or the coupling of STIM1 to Orai1. We detected cholesterol binding to an Orai1 amino-terminal fragment in vitro and to full-length Orai1 in cells. Thus, our data showed that Orai1 senses the amount of cholesterol in the plasma membrane and that the interaction of Orai1 with cholesterol inhibits its activity, thereby limiting SOCE. PMID:26814231

  6. Cholesterol biosynthesis modulation regulates dengue viral replication.

    PubMed

    Rothwell, Christopher; Lebreton, Aude; Young Ng, Chuan; Lim, Joanne Y H; Liu, Wei; Vasudevan, Subhash; Labow, Mark; Gu, Feng; Gaither, L Alex

    2009-06-20

    We performed a focused siRNA screen in an A549 dengue type 2 New Guinea C subgenomic replicon cell line (Rluc-replicon) that contains a Renilla luciferase cassette. We found that siRNA mediated knock down of mevalonate diphospho decarboxylase (MVD) inhibited viral replication of the Rluc-replicon and DEN-2 NGC live virus replication in A549 cells. When the Rluc-replicon A459 cells were grown in delipidated media the replicon expression was suppressed and MVD knock down could further sensitize Renilla expression. Hymeglusin and zaragozic acid A could inhibit DEN-2 NGC live virus replication in K562 cells, while lovastatin could inhibit DEN-2 NGC live virus replication in human peripheral blood mononuclear cells. Renilla expression could be rescued in fluvastatin treated A549 Rluc-replicon cells after the addition of mevalonate, and partially restored with geranylgeranyl pyrophosphate, or farnesyl pyrophosphate. Our data suggest genetic and pharmacological modulation of cholesterol biosynthesis can regulate dengue virus replication. PMID:19419745

  7. Plasma lipoproteins and lecithin:cholesterol acyltransferase distribution in patients on dialysis.

    PubMed

    McLeod, R; Reeve, C E; Frohlich, J

    1984-04-01

    Plasma lipoproteins and LCAT activity were studied using a single spin density gradient separation and an exogenous substrate enzyme assay in 41 patients on chronic hemodialysis and in 11 normal subjects. The plasma HDL cholesterol was markedly decreased (33 vs. 63 mg/dl, P less than 0.001) while total and LDL-cholesterol were unchanged in the patients. Plasma LCAT activity was significantly lower in the patient group (42 vs. 59 nmoles/4 hr/ml, P less than 0.001), but the distribution of activity (studied in 13 dialysis patients and 12 control subjects) was not different between the two groups: 90% being associated with HDL and VHDL lipoprotein fractions. To examine the possible genetic influence on the development of hypertriglyceridemia in the patient group, we examined the ratio of apolipoproteins E3/E2 and CII/CIII in ten of the patients and another group of 13 control subjects. The frequency of heterozygotes for E3 deficiency was not different between the patient (one of ten) and the control (two of 13) groups. While the patient group had lower CII/CIII ratio, the figures did not reach statistical significance. The low LCAT activity in the face of higher plasma triglycerides and low HDL may contribute to impaired lipolysis previously documented in uremic patients. A follow-up study performed 1 year after the initial study confirmed the decreased HDL (51 vs. 71 mg/dl, P less than 0.01) and LCAT activity (50 vs. 59 nmoles/hr/ml, P less than 0.02) in an exogenous substrate system (N = 20). LCAT measured using the endogenous substrate was not significantly different from the control group (49 vs. 55 nmoles/hr/ml).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6482172

  8. Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy

    PubMed Central

    Ford, Ian; Murray, Heather; Packard, Chris J.

    2016-01-01

    Background— Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. Methods and Results— The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80–0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69–0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. Conclusion— Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies. PMID:26864092

  9. Characteristics of High-density Lipoprotein Subclasses Distribution for Subjects with Desirable Total Cholesterol Levels

    PubMed Central

    2011-01-01

    Background To investigate alteration of high density lipoproteins (HDL) subclasses distribution in different total cholesterol (TC) levels, mainly the characteristics of HDL subclasses distribution in desirable TC levels and analyze the related mechanisms. Methods ApoA-I contents of plasma HDL subclasses were determined by 2-dimensional gel electrophoresis coupled with immunodetection. 486 Chinese Adults subjects were assigned to different TC groups according to the third Report of NCEP (ATP- III) guidelines. Results The increase in contents of small preβ1-HDL, HDL3c, HDL3b, and HDL3a particles clustered and reduce in HDL2b with increased of TC. The distribution of HDL subclasses have shown abnormality characterized by the lower HDL2b (324.2 mg/L) contents and the higher preβ1-HDL (90.4 mg/L) contents for desirable TC Chinese subjects. Among 176 desirable TC subjects, 58.6% subjects with triglyceride (TG) < 2.26 mmol/L, 61.2% subjects with HDL-C ≥1.03 mmol/L and 88.6% subjects with low density lipoprotein cholesterol(LDL-C) < 3.34 mmol/L, and the profile of HDL subclasses distribution for above these subjects was reasonable. Conclusions The particles size of HDL subclasses shifted towards smaller with increased TC levels. The TC was liner with HDL2b contents and those can be reduced 17 mg/L for 0.5 mmol/L increment in TC levels. The HDL subclasses distribution phenotype was not expectation for Chinese Population with desirable TC levels. Thus, from the HDL subclasses distribution point, when assessing the coronary heart disease(CHD) risk not only rely on the TC levels, but also the concentrations of TG, HDL-C and LDL-C must considered in case the potential risk for desirable TC subjects with other plasma lipids metabolism disorders. PMID:21513524

  10. Cholesterol Modulates the Dimer Interface of the β2-Adrenergic Receptor via Cholesterol Occupancy Sites

    PubMed Central

    Prasanna, Xavier; Chattopadhyay, Amitabha; Sengupta, Durba

    2014-01-01

    The β2-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the β2-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the β2-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets. PMID:24655504

  11. Usefulness of High-Density Lipoprotein Cholesterol to Predict Survival in Pulmonary Arterial Hypertension.

    PubMed

    Larsen, Carolyn M; McCully, Robert B; Murphy, Joseph G; Kushwaha, Sudhir S; Frantz, Robert P; Kane, Garvan C

    2016-07-15

    It has been suggested that lipoprotein abnormalities may contribute to the pulmonary arteriolar dysfunction observed in pulmonary arterial hypertension (PAH). High-density lipoprotein cholesterol (HDL) has vasodilatory, anti-inflammatory, and endothelial protective properties. We hypothesized that a higher serum HDL level may be advantageous for survival in PAH and that the serum HDL level at diagnosis would be an independent predictor of survival in PAH and be additive to previously validated predictors of survival. This study included all patients with PAH seen at the Mayo Clinic Pulmonary Hypertension Clinic from January 1, 1995, to December 31, 2009, who had a baseline HDL measurement. Mortality was analyzed over 5 years using the Kaplan-Meier method. Univariate and multivariable Cox proportional hazards ratios were calculated to evaluate the relation between baseline HDL level and survival. HDL levels were available for 227 patients. Higher HDL levels were associated with significantly lower mortality. Patients with an HDL >54 mg/dl at diagnosis had a 5-year survival of 59%. By comparison those with an HDL <34 mg/dl had a 5-year survival of 30%. On multivariate analysis, higher HDL was associated with an age-adjusted risk ratio for death of 0.78 (CI 0.67 to 0.91; p <0.01) per 10 mg/dl increase. In conclusion, HDL was an independent predictor of survival in PAH. PMID:27291969

  12. Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells.

    PubMed

    Palmer, Anna M; Murphy, Nuala; Graham, Annette

    2004-03-01

    High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from 'foam cell' macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage 'foam cells' with TGRL (0-200 microg/ml, 0-24 h) inhibited the efflux of exogenously radiolabelled ([3H]), endogenously synthesised ([14C]) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process--namely apoE, ABCA1, SR-B1 and caveolin-1--were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway. PMID:15177121

  13. What's Cholesterol?

    MedlinePlus

    ... Most cholesterol is LDL (low-density lipoprotein) cholesterol. LDL cholesterol is more likely to clog blood vessels because ... Here's a way to remember the difference: the LDL cholesterol is the bad kind, so call it "lousy" ...

  14. Cholesterol modulates bitter taste receptor function.

    PubMed

    Pydi, Sai Prasad; Jafurulla, Md; Wai, Lisa; Bhullar, Rajinder P; Chelikani, Prashen; Chattopadhyay, Amitabha

    2016-09-01

    Bitter taste perception in humans is believed to act as a defense mechanism against ingestion of potential toxic substances. Bitter taste is perceived by 25 distinct bitter taste receptors (T2Rs) which belong to the family of G protein-coupled receptors (GPCRs). In the overall context of the role of membrane lipids in GPCR function, we show here that T2R4, a representative member of the bitter taste receptor family, displays cholesterol sensitivity in its signaling function. In order to gain further insight into cholesterol sensitivity of T2R4, we mutated two residues Tyr114(3.59) and Lys117(3.62) present in the cholesterol recognition amino acid consensus (CRAC) motif in T2R4 with alanines. We carried out functional characterization of the mutants by calcium mobilization, followed by cholesterol depletion and replenishment. CRAC motifs in GPCRs have previously been implicated in preferential cholesterol association. Our analysis shows that the CRAC motif represents an intrinsic feature of bitter taste receptors and is conserved in 22 out of 25 human T2Rs. We further demonstrate that Lys117, an important CRAC residue, is crucial in the reported cholesterol sensitivity of T2R4. Interestingly, cholesterol sensitivity of T2R4 was observed at quinine concentrations in the lower mM range. To the best of our knowledge, our results represent the first report addressing the molecular basis of cholesterol sensitivity in the function of taste receptors. PMID:27288892

  15. Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport.

    PubMed

    Annema, Wijtske; Tietge, Uwe J F

    2011-06-01

    Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease. PMID:21424685

  16. The very-high-density lipoprotein fraction of rabbit plasma is rich in tissue-derived cholesterol.

    PubMed

    Nanjee, M N; Miller, N E

    1991-11-01

    When plasma from rabbits, which several weeks earlier had been infused with [3H]cholesterol, was subjected to equilibrium density gradient ultracentrifugation, the specific radioactivity of cholesterol in the very-high-density lipoprotein (VHDL) fraction (d 1.22-1.32 g/ml) was three to 8-fold greater (mean, 5.5-fold; P less than 0.001) than that in high-density lipoproteins (HDL; d 1.06-1.21 g/ml). On size exclusion chromatography of plasma, no increase in specific radioactivity was seen in particles smaller than HDL. These findings suggest that those apolipoprotein-lipid complexes that dissociate from HDL during ultracentrifugation to form the VHDL fraction contain proportionately more tissue-derived cholesterol than do those that are more tightly bound to HDL. PMID:1932106

  17. Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice.

    PubMed

    Park, Tae-Sik; Panek, Robert L; Rekhter, Mark D; Mueller, Sandra Bak; Rosebury, Wendy S; Robertson, Andrew; Hanselman, Jeffrey C; Kindt, Erick; Homan, Reynold; Karathanasis, Sotirios K

    2006-12-01

    Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis. PMID:16458317

  18. Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice.

    PubMed

    Braun, Anne; Yesilaltay, Ayce; Acton, Susan; Broschat, Kay O; Krul, Elaine S; Napawan, Nida; Stagliano, Nancy; Krieger, Monty

    2008-05-01

    SR-BI/apoE double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including hypercholesterolemia, occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, cardiac dysfunction and premature death. Ezetimibe is a FDA-approved, intestinal cholesterol absorption inhibitor that lowers plasma LDL cholesterol in humans and animals and inhibits aortic root atherosclerosis in apoE KO mice, but has not been proven to reduce CHD. Three-week-ezetimibe treatment of dKO mice (0.005% (w/w) in standard chow administered from weaning) resulted in a 35% decrease in cholesterol in IDL/LDL-size lipoproteins, but not in VLDL- and HDL-size lipoproteins. Ezetimibe treatment significantly reduced aortic root (57%) and coronary arterial (68%) atherosclerosis, cardiomegaly (24%) and cardiac fibrosis (57%), and prolonged the lives of the mice (27%). This represents the first demonstration of beneficial effects of ezetimibe treatment on CHD. The dKO mice were similarly treated with SC-435 (0.01% (w/w)), an apical sodium codependent bile acid transporter (ASBT) inhibitor, that blocks intestinal absorption of bile acids, lowers plasma cholesterol in animals, and reduces aortic root atherosclerosis in apoE KO mice. The effects of SC-435 treatment were similar to those of ezetimibe: 37% decrease in ILD/LDL-size lipoprotein cholesterol and 57% prolongation in median lifespan. Thus, inhibition of intestinal absorption of either cholesterol (ezetimibe) or bile acids (SC-435) significantly reduced plasma IDL/LDL-size lipoprotein cholesterol levels and improved survival of SR-BI/apoE dKO mice. The SR-BI/apoE dKO murine model of atherosclerotic occlusive, arterial CHD appears to provide a useful system to evaluate compounds that modulate cholesterol homeostasis and atherosclerosis. PMID:18054357

  19. High-density lipoprotein cholesterol values independently and inversely predict cardiac troponin T and I concentration

    PubMed Central

    Lo Cascio, Claudia; Brocco, Giorgio; Danese, Elisa; Montagnana, Martina; Bassi, Antonella; Caruso, Beatrice; Bovo, Chiara; Salvagno, Gian Luca

    2016-01-01

    Background This retrospective study was planned to establish potential associations between circulating values of cardiac troponins and those of conventional blood lipids. Methods The study population consisted of patients attending an inpatient clinic of the University Hospital of Verona during the year 2015 as part of routine cardiovascular risk assessment. No exclusion criteria were applied. Serum lipids including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) were measured using reference enzymatic techniques, whereas troponin T (TnT) was measured using a high-sensitivity (HS) immunoassay. A second analysis was also performed in the General Hospital of Verona, extracting data from the local laboratory database of all patients in whom troponin I (TnI) and blood lipids were simultaneously measured during the same year. Results In univariate analysis, HS-TnT was found to be associated with age, sex, TC, LDL-C, HDL-C, but not with TG. In multivariate linear regression analysis, age (positive correlation; P<0.001) and HDL-C (negative correlation; P=0.032) remained significantly associated with HS-TnT. The frequency of HS-TnT values >50 ng/L was higher in subjects with HDL-C <1 mmol/L than in those with HDL-C ≥1 mmol/L [odds ratio (OR), 1.84; 95% confidence interval (CI), 1.03–3.32]. The frequency of HS-TnT values >50 ng/L was also higher in elderly subjects than in younger ones (OR, 2.10; 95% CI, 1.15–3.84). The combination of age and HDL-C explained 35% of overall variability of TnT concentration. In the second analysis, HDL-C was also found to be an independent and negative predictor of TnI in multivariate linear regression analysis (P=0.010). The combination of age and HDL-C explained approximately 28% of the overall variability of TnI concentration. Conclusions Our study suggests that HDL-C values inversely predict cardiac troponins concentration irrespective of age

  20. Determining a new formula for calculating low-density lipoprotein cholesterol: data mining approach

    PubMed Central

    Dansethakul, Prabhop; Thapanathamchai, Lalin; Saichanma, Sarawut; Worachartcheewan, Apilak; Pidetcha, Phannee

    2015-01-01

    Low-density lipoprotein cholesterol (LDL-C) is a risk factor of coronary heart diseases. The estimation of LDL-C (LDL-Cal) level was performed using Friedewald's equation for triglyceride (TG) level less than 400 mg/dL. Therefore, the aim of this study is to generate a new formula for LDL-Cal and validate the correlation coefficient between LDL-Cal and LDL-C directly measured (LDL-Direct). A data set of 1786 individuals receiving annual medical check-ups from the Faculty of Medical Technology, Mahidol University, Thailand in 2008 was used in this study. Lipid profiles including total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C) and LDL-C were determined using Roche/Hitachi modular system analyzer. The estimated LDL-C was obtained using Friedewald's equation and the homogenous enzymatic method. The level of TG was divided into 6 groups (TG<200, <300, <400, <500, <600 and < 1000 mg/dL) for constructing the LDL-Cal formula. The pace regression model was used to construct the candidate formula for the LDL-Cal and determine the correlation coefficient (r) with the LDL-Direct. The candidate LDL-Cal formula was generated for 6 groups of TG levels that displayed well correlation between LDL-Cal and LDL-Direct. Interestingly, The TG level was less than 1000 mg/dL, the regression model was able to generate the equation as shown as strong r of 0.9769 with LDL-Direct. Furthermore, external data set (n = 666) with TG measurement (36-1480 mg/dL) was used to validate new formula which displayed high r of 0.971 between LDL-Cal and LDL-direct. This study explored a new formula for LDL-Cal which exhibited higher r of 0.9769 and far beyond the limitation of TG more than 1000 mg/dL and potential used for estimating LDL-C in routine clinical laboratories. PMID:26600746

  1. Association of the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio and concentrations of plasma lipids with high-density lipoprotein subclass distribution in the Chinese population

    PubMed Central

    2010-01-01

    Background To evaluate the relationship between the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio and HDL subclass distribution and to further examine and discuss the potential impact of LDL-C and HDL-C together with TG on HDL subclass metabolism. Results Small-sized preβ1-HDL, HDL3b and HDL3a increased significantly while large-sized HDL2a and HDL2b decreased significantly as the LDL-C/HDL-C ratio increased. The subjects in low HDL-C level (< 1.03 mmol/L) who had an elevation of the LDL-C/HDL-C ratio and a reduction of HDL2b/preβ1-HDL regardless of an undesirable or high LDL-C level. At desirable LDL-C levels (< 3.34 mmol/L), the HDL2b/preβ1-HDL ratio was 5.4 for the subjects with a high HDL-C concentration (≥ 1.55 mmol/L); however, at high LDL-C levels (≥ 3.36 mmol/L), the ratio of LDL-C/HDL-C was 2.8 in subjects, and an extremely low HDL2b/preβ1-HDL value although with high HDL-C concentration. Conclusion With increase of the LDL-C/HDL-C ratio, there was a general shift toward smaller-sized HDL particles, which implied that the maturation process of HDL was blocked. High HDL-C concentrations can regulate the HDL subclass distribution at desirable and borderline LDL-C levels but cannot counteract the influence of high LDL-C levels on HDL subclass distribution. PMID:20615262

  2. Cholesterol-sensitive Modulation of Transcytosis

    PubMed Central

    Leyt, Julieta; Melamed-Book, Naomi; Vaerman, Jean-Pierre; Cohen, Shulamit; Weiss, Aryeh M.

    2007-01-01

    Cholesterol-rich membrane domains (e.g., lipid rafts) are thought to act as molecular sorting machines, capable of coordinating the organization of signal transduction pathways within limited regions of the plasma membrane and organelles. The significance of these domains in polarized postendocytic sorting is currently not understood. We show that dimeric IgA stimulates the incorporation of its receptor into cholesterol-sensitive detergent-resistant membranes confined to the basolateral surface/basolateral endosomes. A fraction of human transferrin receptor was also found in basolateral detergent-resistant membranes. Disrupting these membrane domains by cholesterol depletion (using methyl-β-cyclodextrin) before ligand-receptor internalization caused depolarization of traffic from endosomes, suggesting that cholesterol in basolateral lipid rafts plays a role in polarized sorting after endocytosis. In contrast, cholesterol depletion performed after ligand internalization stimulated cargo transcytosis. It also stimulated caveolin-1 phosphorylation on tyrosine 14 and the appearance of the activated protein in dimeric IgA-containing apical organelles. We propose that cholesterol depletion stimulates the coupling of transcytotic and caveolin-1 signaling pathways, consequently prompting the membranes to shuttle from endosomes to the plasma membrane. This process may represent a unique compensatory mechanism required to maintain cholesterol balance on the cell surface of polarized epithelia. PMID:17392516

  3. Specific Cellular Incorporation of a Pyrene-Labelled Cholesterol: Lipoprotein-Mediated Delivery toward Ordered Intracellular Membranes

    PubMed Central

    Gaibelet, Gérald; Azalbert, Vincent; Bertrand-Michel, Justine; Hamdi, Safouane; Collet, Xavier; Orlowski, Stéphane

    2015-01-01

    In the aim of testing tools for tracing cell trafficking of exogenous cholesterol, two fluorescent derivatives of cholesterol, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), with distinctive chemico-physical characteristics, have been compared for their cell incorporation properties, using two cell models differently handling cholesterol, with two incorporation routes. In the Caco-2 cell model, the cholesterol probes were delivered in bile salt micelles, as a model of intestinal absorption. The two probes displayed contrasting behaviors for cell uptake characteristics, cell staining, and efflux kinetics. In particular, Pyr-met-Chol cell incorporation involved SR-BI, while that of NBD-Chol appeared purely passive. In the PC-3 cell model, which overexpresses lipoprotein receptors, the cholesterol probes were delivered via the serum components, as a model of systemic delivery. We showed that Pyr-met-Chol-labelled purified LDL or HDL were able to specifically deliver Pyr-met-Chol to the PC-3 cells, while NBD-Chol incorporation was independent of lipoproteins. Observations by fluorescence microscopy evidenced that, while NBD-Chol readily stained the cytosolic lipid droplets, Pyr-met-Chol labelling led to the intense staining of intracellular structures of membranous nature, in agreement with the absence of detectable esterification of Pyr-met-Chol. A 48 h incubation of PC-3 cells with either Pyr-met-Chol-labelled LDL or HDL gave same staining patterns, mainly colocalizing with Lamp1, caveolin-1 and CD63. These data indicated convergent trafficking downwards their respective receptors, LDL-R and SR-BI, toward the cholesterol-rich internal membrane compartments, late endosomes and multivesicular bodies. Interestingly, Pyr-met-Chol staining of these structures exhibited a high excimer fluorescence emission, revealing their ordered membrane environment, and indicating that Pyr-met-Chol behaves as a fair cholesterol tracer

  4. Specific cellular incorporation of a pyrene-labelled cholesterol: lipoprotein-mediated delivery toward ordered intracellular membranes.

    PubMed

    Gaibelet, Gérald; Allart, Sophie; Tercé, François; Azalbert, Vincent; Bertrand-Michel, Justine; Hamdi, Safouane; Collet, Xavier; Orlowski, Stéphane

    2015-01-01

    In the aim of testing tools for tracing cell trafficking of exogenous cholesterol, two fluorescent derivatives of cholesterol, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), with distinctive chemico-physical characteristics, have been compared for their cell incorporation properties, using two cell models differently handling cholesterol, with two incorporation routes. In the Caco-2 cell model, the cholesterol probes were delivered in bile salt micelles, as a model of intestinal absorption. The two probes displayed contrasting behaviors for cell uptake characteristics, cell staining, and efflux kinetics. In particular, Pyr-met-Chol cell incorporation involved SR-BI, while that of NBD-Chol appeared purely passive. In the PC-3 cell model, which overexpresses lipoprotein receptors, the cholesterol probes were delivered via the serum components, as a model of systemic delivery. We showed that Pyr-met-Chol-labelled purified LDL or HDL were able to specifically deliver Pyr-met-Chol to the PC-3 cells, while NBD-Chol incorporation was independent of lipoproteins. Observations by fluorescence microscopy evidenced that, while NBD-Chol readily stained the cytosolic lipid droplets, Pyr-met-Chol labelling led to the intense staining of intracellular structures of membranous nature, in agreement with the absence of detectable esterification of Pyr-met-Chol. A 48 h incubation of PC-3 cells with either Pyr-met-Chol-labelled LDL or HDL gave same staining patterns, mainly colocalizing with Lamp1, caveolin-1 and CD63. These data indicated convergent trafficking downwards their respective receptors, LDL-R and SR-BI, toward the cholesterol-rich internal membrane compartments, late endosomes and multivesicular bodies. Interestingly, Pyr-met-Chol staining of these structures exhibited a high excimer fluorescence emission, revealing their ordered membrane environment, and indicating that Pyr-met-Chol behaves as a fair cholesterol tracer

  5. Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells.

    PubMed

    Oram, J F

    1983-01-01

    Ultracentrifugally isolated high density lipoprotein (HDL) particles of d greater than 1.125 g/ml promote net transport of cholesterol from cultured cells. Consequently, when cultured human fibroblasts and arterial smooth muscle cells were incubated with HDL3 (d = 1.125-1.21 g/ml) and "very high" density lipoprotein (VHDL, d = 1.21-1.25 g/ml), low density lipoprotein (LDL) receptor activity was induced and the rate of LDL degradation by the cells was increased. Enhancement of LDL degradation by HDL3 and VHDL was sustained over incubation periods of 5 days at medium LDL concentrations greater than needed to saturate the LDL receptors. Even during these long-term incubations with LDL, HDL3 and VHDL caused marked reductions in cellular cholesterol content. Thus, an increase in the rate of cholesterol transport from cells may lead to a steady-state decrease in cellular cholesterol content and a sustained increase in the rate of clearance of LDL from the extracellular fluid. In contrast to the effects of HDL3 and VHDL, the major subclasses of HDL2 (HDL2b, d = 1.063-1.100 g/ml; HDL2a, d = 1.100-1.125 g/ml) did not promote net cholesterol transport from cells. Moreover, by apparent direct blockage of the effects that HDL3 and VHDL had on cholesterol transport, HDL2 reversed the increased rate of LDL degradation induced by HDL3 and VHDL. These results suggest that the relative proportion of HDL subfractions in the extracellular fluid may be an important determinant of both the rate of cholesterol transport from cells and the rate of receptor-mediated catabolism of LDL. PMID:6312947

  6. Dietary Cholesterol Modulates Pathogen Blocking by Wolbachia

    PubMed Central

    Caragata, Eric P.; Rancès, Edwige; Hedges, Lauren M.; Gofton, Alexander W.; Johnson, Karyn N.; O'Neill, Scott L.; McGraw, Elizabeth A.

    2013-01-01

    The bacterial endosymbiont Wolbachia pipientis protects its hosts from a range of pathogens by limiting their ability to form infections inside the insect. This “pathogen blocking” could be explained by innate immune priming by the symbiont, competition for host-derived resources between pathogens and Wolbachia, or the direct modification of the cell or cellular environment by Wolbachia. Recent comparative work in Drosophila and the mosquito Aedes aegypti has shown that an immune response is not required for pathogen blocking, implying that there must be an additional component to the mechanism. Here we have examined the involvement of cholesterol in pathogen blocking using a system of dietary manipulation in Drosophila melanogaster in combination with challenge by Drosophila C virus (DCV), a common fly pathogen. We observed that flies reared on cholesterol-enriched diets infected with the Wolbachia strains wMelPop and wMelCS exhibited reduced pathogen blocking, with viral-induced mortality occurring 2–5 days earlier than flies reared on Standard diet. This shift toward greater virulence in the presence of cholesterol also corresponded to higher viral copy numbers in the host. Interestingly, an increase in dietary cholesterol did not have an effect on Wolbachia density except in one case, but this did not directly affect the strength of pathogen blocking. Our results indicate that host cholesterol levels are involved with the ability of Wolbachia-infected flies to resist DCV infections, suggesting that cholesterol contributes to the underlying mechanism of pathogen blocking. PMID:23825950

  7. Hepatic perfusate very low density lipoproteins obtained from fat-fed nonhuman primates stimulate cholesterol esterification in macrophages.

    PubMed

    Soltys, P A; Gump, H; Hennessy, L; Mazzone, T; Carey, K D; McGill, H C; Getz, G S; Bates, S R

    1988-02-01

    The livers of both baboons and rhesus monkeys fed a high fat, high cholesterol diet secreted very low density lipoproteins (VLDL) that were enriched in cholesteryl ester and apoe as compared to VLDL secreted by the livers of chow-fed animals. Stimulation of macrophage cholesterol esterification by the experimental VLDL was compared to that produced by the standard beta-VLDL obtained from the plasma of a rhesus monkey fed 25% coconut oil plus 2% cholesterol. This standard beta-VLDL stimulated 7- to 10-fold more esterification than did the bovine albumin control. Hepatic VLDL from fat-fed animals stimulated esterification in J774 macrophages 50 to 150% as well as did the standard beta-VLDL, even though hepatic VLDL did not display beta electrophoretic mobility on agarose gel electrophoresis. Plasma VLDL from lard-fed baboons did not exhibit beta electrophoretic mobility but did stimulate esterification in macrophages. Baboons were divided into high and low responders based on the change in plasma cholesterol levels in response to a high fat, high cholesterol diet. Both plasma and hepatic VLDL from high responders stimulated cholesterol esterification, whereas hepatic VLDL obtained from low responders or chow-fed baboons did not stimulate cholesterol esterification in macrophages. There was a strong positive correlation (r = 0.866) between the number of apoE molecules per VLDL particle in VLDL obtained from chow-fed, lard-fed, or coconut oil-fed primates and the rate of cholesterol esterification in macrophages. Our results show that hepatic perfusate VLDL obtained from fat- and cholesterol-fed primates have compositional and functional properties usually ascribed to circulating beta-VLDL, without displaying beta mobility, and indicate that the liver may be an important source of atherogenic lipoproteins. PMID:3367088

  8. Dietary palmitic and oleic acids exert similar effects on serum cholesterol and lipoprotein profiles in normocholesterolemic men and women.

    PubMed

    Ng, T K; Hayes, K C; DeWitt, G F; Jegathesan, M; Satgunasingam, N; Ong, A S; Tan, D

    1992-08-01

    To compare the effects of dietary palmitic acid (16:0) vs oleic acid (18:1) on serum lipids, lipoproteins, and plasma eicosanoids, 33 normocholesterolemic subjects (20 males, 13 females; ages 22-41 years) were challenged with a coconut oil-rich diet for 4 weeks. Subsequently they were assigned to either a palm olein-rich or olive oil-rich diet followed by a dietary crossover during two consecutive 6-week periods. Each test oil served as the sole cooking oil and contributed 23% of dietary energy or two-thirds of the total daily fat intake. Dietary myristic acid (14:0) and lauric acid (12:0) from coconut oil significantly raised all the serum lipid and lipoprotein parameters measured. Subsequent one-to-one exchange of 7% energy between 16:0 (palm olein diet) and 18:1 (olive oil diet) resulted in identical serum total cholesterol (192, 193 mg/dl), low-density lipoprotein cholesterol (LDL-C) (130, 131 mg/dl), high-density lipoprotein cholesterol (HDL-C) (41, 42 mg/dl), and triglyceride (TG) (108, 106 mg/dl) concentrations. Effects attributed to gender included higher HDL in females and higher TG in males associated with the tendency for higher LDL and LDL/HDL ratios in men. However, both sexes were equally responsive to changes in dietary fat saturation. The results indicate that in healthy, normocholesterolemic humans, dietary 16:0 can be exchanged for 18:1 within the range of these fatty acids normally present in typical diets without affecting the serum lipoprotein cholesterol concentration or distribution. In addition, replacement of 12:0 + 14:0 by 16:0 + 18:1, but especially 16:0 or some component of palm olein, appeared to have a beneficial impact on an important index of thrombogenesis, i.e., the thromboxane/prostacyclin ratio in plasma. PMID:1506599

  9. Association of dietary fiber intake with serum total cholesterol and low density lipoprotein cholesterol levels in Urban Asian-Indian adults with type 2 diabetes

    PubMed Central

    Narayan, Shreya; Lakshmipriya, Nagarajan; Vaidya, Ruchi; Bai, Mookambika Ramya; Sudha, Vasudevan; Krishnaswamy, Kamala; Unnikrishnan, Ranjit; Anjana, Ranjit Mohan; Mohan, Viswanathan

    2014-01-01

    Context: There is little data correlating dietary fibre (DF) intake and cardiovascular risk in Asian Indians with diabetes. Aim: To assess the DF intake and its association with lipid profile (total serum cholesterol and low density lipoprotein [LDL] - cholesterol levels) in urban Asian Indians with diabetes. Subjects and Methods: Dietary assessment using validated Food Frequency Questionnaire was conducted in 1191 free-living adults with known diabetes in the Chennai Urban Rural Epidemiology Study. Subjects taking medication for dyslipidemia, and those with cardiovascular disease and implausible energy intake (n = 262) were excluded, leaving 929 participants. Anthropometric and relevant biochemical parameters were measured using standardized techniques. Results: Diabetic individuals who consumed DF < median intake (29 g/day) had a higher prevalence of hypercholesterolemia (49.5% vs. 40.1% [P = 0.01]) and higher LDL cholesterol (46.2% vs. 35.5% [P = 0.001]) than those in the > median intake of DF group. The risk of hypercholesterolemia (odds ratio [OR] =1.38 [95% confidence interval [CI]: 1.02–1.85], P = 0.04), and high LDL cholesterol (OR: 1.43 [95% CI: 1.06–1.94], P = 0.02) was higher among those whose DF intake was less than the median. Serum triglycerides and high density lipoprotein cholesterol were not associated with DF intake. The main sources of DF were vegetables and legumes. Conclusion: In urban Asian Indians with diabetes, lower DF intake is positively related to total cholesterol and LDL cholesterol levels. PMID:25285277

  10. Consistently high plasma high-density lipoprotein-cholesterol levels in children in Spain, a country with low cardiovascular mortality.

    PubMed

    Garcés, Carmen; Gil, Angel; Benavente, Mercedes; Viturro, Enrique; Cano, Beatriz; de Oya, Manuel

    2004-08-01

    Coronary heart disease (CHD) mortality is relatively low in Spain compared with other developed countries and has remained low despite an apparent increase in mean plasma cholesterol concentration in adults over the last several years. It is accepted that pathologic processes related to arteriosclerosis development begin in childhood and seem to be related to the presence of cardiovascular risk factors at this age. High-density lipoprotein-cholesterol (HDL-C) levels in children have been inversely correlated with the incidence of coronary heart disease in the different countries studied. Childhood plasma lipoprotein profile might contribute to the low coronary heart disease mortality in Spain. Thus, we analyzed data on lipid levels over time in schoolchildren in Spain in the last decade. Plasma lipid levels were analyzed in prepuberal children (6 to 8 years) in 3 school-based surveys performed by our group in Madrid in 1987, 1993, and 1999. A significant increase in plasma total cholesterol (P < .05) and low-density lipoprotein-cholesterol (LDL-C) (P < .01) levels in prepuberal children was observed over the last decade. However, the mean concentration of plasma HDL-C remained stable and very high. These high levels of plasma HDL-C in Spanish school children may help to explain why the coronary heart disease mortality rate in Spain is low compared with that in other developed countries. PMID:15281016

  11. Autophagy-mediated longevity is modulated by lipoprotein biogenesis

    PubMed Central

    Seah, Nicole E.; de Magalhaes Filho, C. Daniel; Petrashen, Anna P.; Henderson, Hope R.; Laguer, Jade; Gonzalez, Julissa; Dillin, Andrew; Hansen, Malene; Lapierre, Louis R.

    2016-01-01

    ABSTRACT Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis. PMID:26671266

  12. Effects of human follicular fluid and high-density lipoproteins on early spermatozoa hyperactivation and cholesterol efflux

    PubMed Central

    Hamdi, Safouane M.; Vieitez, Gérard; Jaspard, Béatrice; Barbaras, Ronald; Perret, Bertrand; Mieusset, Roget; Parinaud, Jean; Collet, Xavier

    2010-01-01

    The preovulatory human follicular fluid contains only HDLs as a lipoprotein class with a typically high proportion of preβ HDL. We first examined the role of follicular fluid and HDL subfractions on human spermatozoa capacitation, a process characterized by a hyperactivation of the flagellar movement and a depletion of plasma membrane cholesterol. Whole follicular fluid and isolated HDL, used at constant free cholesterol concentration, were both able to promote an early flagellar hyperactivation. Moreover, incubation of [3H]cholesterol-labeled spermatozoa with follicular fluid induced a rapid cholesterol efflux from spermatozoa that was confirmed by mass measurements of cholesterol transfer. Using isolated HDL, the cholesterol efflux had a similar time course and represented 70% of that mediated by whole follicular fluid. We then analyzed the time course of radioactive labeling of HDL subfractions. In the first minute of incubation, we found that the preβ HDL fraction incorporated the main part of the radioactivity (60%), with the rest being found in α-HDL, but strikingly, the labeling of α-HDL increased with time at the expense of preβ HDL.Thus, our results indicate that HDLs are involved in both spermatozoa hyperactivation and cholesterol effl ux and suggest the role of preβ-HDL particles as fi rst cellular cholesterol acceptors. PMID:19965575

  13. Cholesterol modulates open probability and desensitization of NMDA receptors

    PubMed Central

    Korinek, Miloslav; Vyklicky, Vojtech; Borovska, Jirina; Lichnerova, Katarina; Kaniakova, Martina; Krausova, Barbora; Krusek, Jan; Balik, Ales; Smejkalova, Tereza; Horak, Martin; Vyklicky, Ladislav

    2015-01-01

    NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the CNS. Although these receptors are in direct contact with plasma membrane, lipid–NMDAR interactions are little understood. In the present study, we aimed at characterizing the effect of cholesterol on the ionotropic glutamate receptors. Whole-cell current responses induced by fast application of NMDA in cultured rat cerebellar granule cells (CGCs) were almost abolished (reduced to 3%) and the relative degree of receptor desensitization was increased (by seven-fold) after acute cholesterol depletion by methyl-β-cyclodextrin. Both of these effects were fully reversible by cholesterol repletion. By contrast, the responses mediated by AMPA/kainate receptors were not affected by cholesterol depletion. Similar results were obtained in CGCs after chronic inhibition of cholesterol biosynthesis by simvastatin and acute enzymatic cholesterol degradation to 4-cholesten-3-one by cholesterol oxidase. Fluorescence anisotropy measurements showed that membrane fluidity increased after methyl-β-cyclodextrin pretreatment. However, no change in fluidity was observed after cholesterol enzymatic degradation, suggesting that the effect of cholesterol on NMDARs is not mediated by changes in membrane fluidity. Our data show that diminution of NMDAR responses by cholesterol depletion is the result of a reduction of the open probability, whereas the increase in receptor desensitization is the result of an increase in the rate constant of entry into the desensitized state. Surface NMDAR population, agonist affinity, single-channel conductance and open time were not altered in cholesterol-depleted CGCs. The results of our experiments show that cholesterol is a strong endogenous modulator of NMDARs. Key points NMDA receptors (NMDARs) are tetrameric cation channels permeable to calcium; they mediate excitatory synaptic transmission in the CNS and their excessive activation can lead to

  14. Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography.

    PubMed

    Kieft, K A; Bocan, T M; Krause, B R

    1991-05-01

    A high-performance gel chromatography (HPGC) system has been developed which allows the unattended on-line determination of lipoprotein cholesterol distribution (VLDL-C, LDL-C, HDL-C), within 40 min, in microliter quantities of plasma using a single, relatively inexpensive column (Superose 6HR). The FAST cholesterol reagent (Sclavo) and a knitted PFTE Kratos reaction coil (Applied Biosystems) were found to provide optimal sensitivity, linearity, resolution, and dispersion characteristics. Validation is provided by comparison to target values for human quality control reference sera, and by comparing the values obtained by HPGC to the beta-quant method (LRC). The utility of the system is illustrated by comparing profiles from seven different species with normal or elevated plasma cholesterol concentrations. This technique allows rapid analysis of samples, regardless of species, without the use of precipitating agents or the ultracentrifuge. It could also be applied for the direct clinical determination of LDL-cholesterol. PMID:2072044

  15. Cholesterol modulates alkaline phosphatase activity of rat intestinal microvillus membranes.

    PubMed

    Brasitus, T A; Dahiya, R; Dudeja, P K; Bissonnette, B M

    1988-06-25

    Experiments were conducted, using a nonspecific lipid transfer protein, to vary the cholesterol/phospholipid molar ratio of rat proximal small intestinal microvillus membranes in order to assess the possible role of cholesterol in modulating enzymatic activities of this plasma membrane. Cholesterol/phospholipid molar ratios from 0.71 to 1.30 were produced from a normal value of 1.05 by incubation with the transfer protein and an excess of either phosphatidylcholine or cholesterol/phosphatidylcholine liposomes for 60 min at 37 degrees C. Cholesterol loading or depletion of the membranes was accompanied by a decrease or increase, respectively, in their lipid fluidity, as assessed by steady-state fluorescence polarization techniques using the lipid-soluble fluorophore 1,6-diphenyl-1,3,5-hexatriene. Increasing the cholesterol/phospholipid molar ratio also decreased alkaline phosphatase specific activity by approximately 20-30%, whereas decreasing this ratio increased this enzymatic activity by 20-30%. Sucrase, maltase, and lactase specific activities were not affected in these same preparations. Since the changes in alkaline phosphatase activity could be secondary to alterations in fluidity, cholesterol, or both, additional experiments were performed using benzyl alcohol, a known fluidizer. Benzyl alcohol (25 mM) restored the fluidity of cholesterol-enriched preparations to control levels, did not change the cholesterol/phospholipid molar ratio, and failed to alter alkaline phosphatase activity. These findings, therefore, indicate that alterations in the cholesterol content and cholesterol/phospholipid molar ratio of microvillus membranes can modulate alkaline phosphatase but not sucrase, maltase, or lactase activities. Moreover, membrane fluidity does not appear to be an important physiological regulator of these enzymatic activities. PMID:3379034

  16. Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice.

    PubMed

    Hellström, Martin; Ericsson, Madelene; Johansson, Bengt; Faraz, Mahmood; Anderson, Fredrick; Henriksson, Roger; Nilsson, Stefan K; Hedman, Håkan

    2016-06-01

    Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wild-type mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans. PMID:27009049

  17. Intensive Lowering of Low-Density Lipoprotein Cholesterol Levels for Primary Prevention of Coronary Artery Disease

    PubMed Central

    Karalis, Dean G.

    2009-01-01

    Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States, and a high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CAD. Current guidelines recommend the use of statins to lower LDL-C levels for the primary prevention of CAD based on an individual's risk factor profile and baseline LDL-C level. For moderaterisk individuals, those with 2 or more major risk factors for CAD and a Framingham risk score of 10% to 20%, the recommendation is to use a statin to lower LDL-C levels to less than 130 mg/dL. However, up to 40% of individuals who develop CAD have LDL-C levels lower than this cutoff. In 2004, the National Cholesterol Education Program Adult Treatment Panel III guidelines were updated to include an LDL-C goal of less than 100 mg/dL for individuals at moderately high risk of developing CAD. The guidelines identified several risk factors that when present would favor the use of pharmacological therapy to achieve this more aggressive LDL-C goal. This review evaluates the evidence supporting an LDL-C target of less than 100 mg/dL for moderately high-risk individuals and reviews those risk factors that when present help identify patients who would benefit from achieving this lower LDL-C goal. English-language publications in MEDLINE and references from relevant articles published between January 1, 1980, and November 30, 2008, were reviewed. Main keywords searched were coronary artery disease, hyperlipidemia, statins, cardiac risk factors, inflammatory markers, metabolic syndrome, and coronary artery calcium. PMID:19339653

  18. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High--Density Lipoprotein Intervention Trial.

    PubMed

    Boden, W E

    2000-12-21

    The Framingham Heart Study found that high-density lipoprotein cholesterol (HDL-C) was the most potent lipid predictor of coronary artery disease risk in men and women >49 years of age. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), in which subjects were randomized to treatment with lovastatin or placebo, also reported a striking benefit of treatment, particularly in patients with HDL-C < or =35 mg/dL at baseline. Treatment with lovastatin was associated with a remarkable 45% reduction in events for this group. The Veterans Affairs HDL Intervention Trial (VA-HIT) randomized subjects to gemfibrozil or placebo. A high proportion of enrolled subjects with low HDL-C also had characteristics of the dysmetabolic syndrome. HDL-C likewise increased by 6% on treatment, total cholesterol was reduced by 4% and triglycerides by 31%. There was no change in low-density lipoprotein cholesterol (LDL-C) levels. These changes in lipid were associated with a cumulative 22% reduction in the trial primary endpoint of all-cause mortality and nonfatal myocardial infarction (MI). Additionally, significant reductions in secondary endpoints including death from coronary artery disease, nonfatal MI, stroke, transient ischemic attack, and carotid endarterectomy were associated with the increase in HDL-C. In VA-HIT, for every 1% increase in HDL-C, there was a 3% reduction in death or MI, a therapeutic benefit that eclipses the benefit associated with LDL-C reduction. PMID:11374850

  19. Association of lecithin-cholesterol acyltransferase activity measured as a serum cholesterol esterification rate and low-density lipoprotein heterogeneity with cardiovascular risk: a cross-sectional study.

    PubMed

    Tani, Shigemasa; Takahashi, Atsuhiko; Nagao, Ken; Hirayama, Atsushi

    2016-06-01

    The cholesterol-esterifying enzyme, lecithin-cholesterol acyltransferase (LCAT), is believed to play a key role in reverse cholesterol transport. However, recent investigations have demonstrated that higher LCAT activity levels increase the formation of triglyceride (TG)-rich lipoproteins (TRLs) and atherogenesis. We hypothesized that higher LCAT activity measured as a serum cholesterol esterification rate by the endogenous substrate method might increase the formation of TRLs and thereby alter low-density lipoprotein (LDL) heterogeneity. The estimated LDL particle size [relative LDL migration (LDL-Rm)] was measured by polyacrylamide gel electrophoresis with the LipoPhor system (Joko, Tokyo, Japan) in 538 consecutive patients with at least risk factor for atherosclerosis. Multivariate regression analysis after adjustments for traditional risk factors identified elevated TRL-related marker (TG, remnant-like particle cholesterol, apolipoprotein C-II, and apolipoprotein C-III) levels as independent predictors of smaller-sized LDL particle size, both in the overall subject population and in the subset of patients with serum LDL cholesterol levels of <100 mg/dL. Area under the receiver operating characteristic curve of the LCAT activity (0.79; sensitivity 60 %; specificity 84.8 %) was observed for the evaluation of the indicators of an LDL-Rm value of ≥0.40, which suggests the presence of large amounts of small-dense LDL. The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in LDL particle size. Therefore, to reduce the risk of atherosclerotic cardiovascular disease, it may be of importance to pay attention not only to a quantitative change in the serum LDL-C, but also to the LCAT activity which is possibly associated with LDL heterogeneity. PMID:25894629

  20. Increased hepatic cholesterol esterification with essential fatty acid deficiency (EFAD): relationship to plasma lipoprotein (LP) cholesterol content

    SciTech Connect

    Ney, D.M.; Ziboh, V.A.; Schneeman, B.O.

    1986-03-01

    EFAD in the rat is associated with hepatic accumulation of esterified cholesterol and altered distribution of cholesterol between plasma and hepatic tissue. Little is known regarding the impact of EFAD on LP composition. To determine the relationship between hepatic cholesterol esterification and plasma lP composition in control (C) and EFAD male Wistar rats, the authors induced EFAD with continuous intragastric (IG) infusion of EFA-free solutions containing 3.5% of calories as triolein for 7 and 14 days. C animals received IG infusion of solutions containing 3.5% of calories as linoleic acid. Data in the EFAD groups reveal: (i) marked decreases in hepatic EFAs and increases in monoenoic acids; (ii) progressive increases in hepatic content of triglyceride and esterified cholesterol with 7 and 14 days of feeding; (iii) assay of acyl CoA:cholesterol acyltransferase activity in hepatic tissue using /sup 14/C-cholesterol demonstrates an increase in hepatic cholesterol esterification when compared to C animals. Increased hepatic cholesterol esterification correlates with elevated levels of esterified cholesterol in plasma VLDL and HDL particles. These data indicate that the elevated levels of cholesterol esters in LP particles is due, at least in part, to increased hepatic cholesterol esterification with EFAD.

  1. An in-silico model of lipoprotein metabolism and kinetics for the evaluation of targets and biomarkers in the reverse cholesterol transport pathway.

    PubMed

    Lu, James; Hübner, Katrin; Nanjee, M Nazeem; Brinton, Eliot A; Mazer, Norman A

    2014-03-01

    High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the

  2. Dietary Squalene Increases High Density Lipoprotein-Cholesterol and Paraoxonase 1 and Decreases Oxidative Stress in Mice

    PubMed Central

    Gabás-Rivera, Clara; Barranquero, Cristina; Martínez-Beamonte, Roberto; Navarro, María A.; Surra, Joaquín C.; Osada, Jesús

    2014-01-01

    Background and Purpose Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role on lipid plasma parameters and the influence of genotype on this effect need to be addressed. Experimental Approaches Three male mouse models (wild-type, Apoa1- and Apoe- deficient) were fed chow semisynthetic diets enriched in squalene to provide a dose of 1 g/kg during 11 weeks. After this period, their plasma parameters and lipoprotein profiles were analyzed. Key Results Squalene administration at a dose of 1 g/kg showed decreased reactive oxygen species in lipoprotein fractions independently of the animal background and caused an specific increase in high density lipoprotein (HDL)-cholesterol levels, accompanied by an increase in phosphatidylcholine and paraoxonase 1 and no changes in apolipoproteins A1 and A4 in wild-type mice. In these mice, the cholesterol increase was due to its esterified form and associated with an increased hepatic expression of Lcat. These effects were not observed in absence of apolipoprotein A1. The increases in HDL- paraoxonase 1 were translated into decreased plasma malondialdehyde levels depending on the presence of Apolipoprotein A1. Conclusions and Implications Dietary squalene promotes changes in HDL- cholesterol and paraoxonase 1 and decreases reactive oxygen species in lipoproteins and plasma malondialdehyde levels, providing new benefits of its intake that might contribute to explain the properties of virgin olive oil, although the phenotype related to apolipoproteins A1 and E may be particularly relevant. PMID:25117703

  3. Gender differences in 7 years trends in cholesterol lipoproteins and lipids in India: Insights from a hospital database

    PubMed Central

    Gupta, Rajeev; Sharma, Madhawi; Goyal, Neeraj Krishna; Bansal, Preeti; Lodha, Sailesh; Sharma, Krishna Kumar

    2016-01-01

    Objective: To determine gender differences and secular trends in total, low-density lipoprotein (LDL) and high DL (HDL) cholesterol and triglycerides using a large hospital database in India. Methods: All blood lipid tests evaluated from July 2007 to December 2014 were analyzed. Details of gender and age were available. Statin therapy was obtained at two separate periods. Trends were calculated using linear regression and Mantel-Haenszel X2. Results: Data of 67395 subjects (men 49,904, women 17,491) aged 51 ± 12 years were analyzed. Mean levels (mg/dl) were total cholesterol 174.7 ± 45, LDL cholesterol 110.7 ± 38, non-HDL cholesterol 132.1 ± 44.8, HDL cholesterol 44.1 ± 10, triglycerides 140.8 ± 99, and total: HDL cholesterol 4.44 ± 1.5. Various dyslipidemias in men/women were total cholesterol ≥200 mg/dl 25.4/36.4%, LDL cholesterol ≥130 mg/dl 28.1/35.0% and ≥100 mg/dl 54.4/66.4%, non-HDL cholesterol ≥160 mg/dl 25.5/29.6%, HDL cholesterol <40/50 mg/dl 54.4/64.4%, and triglycerides ≥150 mg/dl 34.0/26.8%. Cholesterol lipoproteins declined over 7 years with greater decline in men versus women for cholesterol (Blinearregression = −0.82 vs. −0.33, LDL cholesterol (−1.01 vs. −0.65), non-HDL cholesterol (−0.88 vs. −0.52), and total: HDL cholesterol (−0.02 vs. −0.01). In men versus women there was greater decline in prevalence of hypercholesterolemia (X2trend 74.5 vs. 1.60), LDL cholesterol ≥130 mg/dl (X2trend 415.5 vs. 25.0) and ≥100 mg/dl (X2trend 501.5 vs. 237.4), non-HDL cholesterol (X2trend 77.4 vs. 6.85), total: HDL cholesterol (X2trend 212.7 vs. 10.5) and high triglycerides (X2trend 10.8 vs. 6.15) (P < 0.01). Use of statins was in 2.6% (36/1405) in 2008 and 9.0% (228/2527) in 2014 (P < 0.01). Statin use was significantly lower in women (5.8%) than men (10.3%). Conclusions: In a large hospital - database we observed greater hypercholesterolemia and low HDL cholesterol in women. Mean levels and prevalence of high total, LDL, non

  4. Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction.

    PubMed

    Henry, Courtney A; Lyon, Ronald A; Ling, Hua

    2016-01-01

    Multiple categories of medications have been developed to manage lipid profiles and reduce the risk of cardiovascular events in patients with heart disease. However, currently marketed medications have not solved the problems associated with preventing and treating cardiovascular diseases completely. A substantial population of patients cannot take advantage of statin therapy due to statin intolerance, heart failure, or kidney hemodialysis, suggesting a need for additional effective agents to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDL-C-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. By inactivating PCSK9, evolocumab upregulates LDL receptors causing increased catabolism of LDL-C and the consequent reduction of LDL-C levels in blood. Overall, evolocumab has had notable efficacy, with LDL-C reduction ranging from 53% to 75% in monotherapy and combination therapies, and is associated with minor adverse effects. However, studies regarding the ability of evolocumab to reduce mortality as well as long-term safety concerns are limited. The fact that the drug was introduced at a cost much higher than the existing medications and shows a low incremental mortality benefit suggests that many payers will consider evolocumab to have an unfavorable cost-benefit ratio. PMID:27143910

  5. Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction

    PubMed Central

    Henry, Courtney A; Lyon, Ronald A; Ling, Hua

    2016-01-01

    Multiple categories of medications have been developed to manage lipid profiles and reduce the risk of cardiovascular events in patients with heart disease. However, currently marketed medications have not solved the problems associated with preventing and treating cardiovascular diseases completely. A substantial population of patients cannot take advantage of statin therapy due to statin intolerance, heart failure, or kidney hemodialysis, suggesting a need for additional effective agents to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDL-C-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. By inactivating PCSK9, evolocumab upregulates LDL receptors causing increased catabolism of LDL-C and the consequent reduction of LDL-C levels in blood. Overall, evolocumab has had notable efficacy, with LDL-C reduction ranging from 53% to 75% in monotherapy and combination therapies, and is associated with minor adverse effects. However, studies regarding the ability of evolocumab to reduce mortality as well as long-term safety concerns are limited. The fact that the drug was introduced at a cost much higher than the existing medications and shows a low incremental mortality benefit suggests that many payers will consider evolocumab to have an unfavorable cost–benefit ratio. PMID:27143910

  6. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control?

    PubMed

    Zimmerman, Marj P

    2015-11-01

    Despite advances in the approach toward treating hypercholesterolemia and widespread access to statin medications, not all people are able to reach target low-density lipoprotein cholesterol (LDL-C) levels to reduce their cardiovascular risk. Some of the reasons include the inability to tolerate statin therapy, LDL-C levels that remain high even in the presence of statin therapy, and a familial disorder that is characterized by extremely high levels of LDL-C. A new therapeutic class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, represents a novel and promising approach to reducing LDL-C levels using a mechanism at the LDL receptor level. The recent approval of the first 2 PCSK9 inhibitors and the anticipated approval of the third agent in this class within approximately 1 year may provide clinicians powerful new weapons to lower LDL-C levels in patients who are not satisfactorily managed with statins. However, the results of long-term studies of the ability of these new medications to influence cardiovascular outcomes will not be known for several years. PMID:26702335

  7. How Do PCSK9 Inhibitors Stack Up to Statins for Low-Density Lipoprotein Cholesterol Control?

    PubMed Central

    Zimmerman, Marj P.

    2015-01-01

    Despite advances in the approach toward treating hypercholesterolemia and widespread access to statin medications, not all people are able to reach target low-density lipoprotein cholesterol (LDL-C) levels to reduce their cardiovascular risk. Some of the reasons include the inability to tolerate statin therapy, LDL-C levels that remain high even in the presence of statin therapy, and a familial disorder that is characterized by extremely high levels of LDL-C. A new therapeutic class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, represents a novel and promising approach to reducing LDL-C levels using a mechanism at the LDL receptor level. The recent approval of the first 2 PCSK9 inhibitors and the anticipated approval of the third agent in this class within approximately 1 year may provide clinicians powerful new weapons to lower LDL-C levels in patients who are not satisfactorily managed with statins. However, the results of long-term studies of the ability of these new medications to influence cardiovascular outcomes will not be known for several years. PMID:26702335

  8. Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

    PubMed

    Schwab, K Otfried; Doerfer, Jürgen; Hungele, Andreas; Scheuing, Nicole; Krebs, Andreas; Dost, Axel; Rohrer, Tilman R; Hofer, Sabine; Holl, Reinhard W

    2015-12-01

    Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction. PMID:26427965

  9. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.

    PubMed

    Hausenloy, D J; Yellon, D M

    2008-11-01

    The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and

  10. Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

    PubMed Central

    Nagiec, Marek M.; Skepner, Adam P.; Negri, Joseph; Eichhorn, Michelle; Kuperwasser, Nicolas; Comer, Eamon; Muncipinto, Giovanni; Subramanian, Aravind; Clish, Clary; Musunuru, Kiran; Duvall, Jeremy R.; Foley, Michael; Perez, Jose R.; Palmer, Michelle A. J.

    2015-01-01

    Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging. PMID:25811180

  11. Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study

    PubMed Central

    Cougnard-Grégoire, Audrey; Delyfer, Marie-Noëlle; Korobelnik, Jean-François; Rougier, Marie-Bénédicte; Le Goff, Mélanie; Dartigues, Jean-François; Barberger-Gateau, Pascale; Delcourt, Cécile

    2014-01-01

    Background Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD. Methods The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data. Results After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use. Conclusions This study suggests that

  12. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

    PubMed Central

    Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ

    2009-01-01

    Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma

  13. Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters.

    PubMed

    Zong, Chuanlong; Song, Guohua; Yao, Shutong; Li, Luqin; Yu, Yang; Feng, Lei; Guo, Shoudong; Luo, Tian; Qin, Shucun

    2012-06-01

    Hydrogen (dihydrogen; H(2)) has an antiatherosclerotic effect in apolipoprotein (apo) E knockout mice. The goals of this study were to further characterize the effects of H(2) on the content, composition, and biological activities of plasma lipoproteins in golden hamsters. Plasma analysis by enzymatic method and fast protein liquid chromatography showed that 4-week intraperitoneal injection of hydrogen-saturated saline remarkably decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels in high-fat diet-fed hamsters. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of apolipoproteins from ultracentrifugally isolated plasma lipoproteins revealed a marked decrease of apo B100 and apo B48 in LDL. A profound decrease of apo E level in very low-density lipoprotein was also observed. Besides, we determined the functional quality of high-density lipoprotein (HDL) particles isolated from H(2)-treated and control mice. H(2) significantly improved HDL functionality assessed in 2 independent ways, namely, (1) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [(3)H]cholesterol efflux and (2) protection against LDL oxidation as a measure of Cu(2+)-induced thiobarbituric acid reactive substances formation. Administration of hydrogen-saturated saline decreases plasma LDL cholesterol and apo B levels and improves hyperlipidemia-injured HDL functions, including the capacity of enhancing cellular cholesterol efflux and playing antioxidative properties, in high-fat diet-fed hamsters. PMID:22153840

  14. Reduction in Postoperative High-Density Lipoprotein Cholesterol Levels in Children Undergoing the Fontan Operation

    PubMed Central

    Argraves, W. Scott; Graham, Eric M.; Slate, Elizabeth H.; Atz, Andrew M.; Bradley, Scott M.; McQuinn, Tim C.; Wilkerson, Brent A.; Wing, Shane B.

    2015-01-01

    Despite the emerging relevance of high-density lipoprotein (HDL) in the inflammatory cascade and vascular barrier integrity, HDL levels in children undergoing cardiac surgery are unexplored. As a measure of HDL levels, the HDL-cholesterol (HDL-C) in single-ventricle patients was quantified before and after the Fontan operation, and it was determined whether relationships existed between the duration and the type of postoperative pleural effusions. The study prospectively enrolled 12 children undergoing the Fontan operation. Plasma HDL-C levels were measured before and after cardiopulmonary bypass. The outcome variables of interest were the duration and type of chest tube drainage (chylous vs. nonchylous). The Kendall rank correlation coefficient and the Wilcoxon rank sum test were used. There were 11 complete observations. The median preoperative HDL-C level for all the subjects was 30 mg/dl (range, 24–53 mg/dl), and the median postcardiopulmonary bypass level was 21 mg/dl (range, 14–46 mg/dl) (p = 0.004). There was a tendency toward a moderate inverse correlation (–0.42) between the postcardiopulmonary bypass HDL-C level and the duration of chest tube drainage, but the result was not statistically significant (p = 0.07). In the chylous effusion group, the median postcardiopulmonary bypass HDL-C tended to be lower (16 vs. 23 mg/dl; p = 0.09). After the Fontan operation, the plasma HDL-C levels in children are significantly reduced. It is reasonable to conclude that the reduction in HDL-C reflects reduced plasma levels of HDL particles, which may have pertinent implications in postoperative pleural effusions given the antiinflammatory and endothelial barrier functions of HDL. PMID:22411716

  15. Roles of High-Density Lipoprotein Cholesterol in Patients With Acute Myocardial Infarction

    PubMed Central

    Lee, Cheol Hyun; Woo, Jong Shin; Park, Chang Bum; Cho, Jin Man; Ahn, Young Keun; Kim, Chong Jin; Jeong, Myung Ho; Kim, Weon

    2016-01-01

    Abstract Many observational studies showed hogh-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular (CV) outcome. However, recent large clinical trials evaluating therapies to raise HDL-C level in those already on statin therapy have been discouraging. This complexity is not well-known. A total of 28,357 acute myocardial infarction (AMI) patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR), which was a prospective, multicenter, nationwide, web-based database of AMI in Korea. From this registry, we evaluated 3574 patients with AMI who have follow-up HDL-C level to investigate its association with clinical outcomes. The primary endpoint was the relationship between follow-up change in HDL-C and a 12-month composite of major adverse cardiac events (MACEs). Patients with initial HDL-C ≥ 40 mg/dL showed significantly lower rates of 12-month MACEs, especially cardiac and all-cause mortalities (P < 0.001). When patients were stratified into 4 groups according to the change of HDL-C, patients with decreasing HDL-C showed significantly higher rates of 12-month MACEs as comparable with patients with increasing HLD-C. A multivariate analysis indicated that HDL-C level was a significant predictor of CV events (hazard ratio, 1.38; 95% confidence interval, 1.12–1.71) after correcting for confounding variables. The follow-up change in HDL-C level was significantly related with CV outcomes in patients with AMI. PMID:27149442

  16. APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema.

    PubMed

    Burkart, Kristin M; Manichaikul, Ani; Wilk, Jemma B; Ahmed, Firas S; Burke, Gregory L; Enright, Paul; Hansel, Nadia N; Haynes, Demondes; Heckbert, Susan R; Hoffman, Eric A; Kaufman, Joel D; Kurai, Jun; Loehr, Laura; London, Stephanie J; Meng, Yang; O'Connor, George T; Oelsner, Elizabeth; Petrini, Marcy; Pottinger, Tess D; Powell, Charles A; Redline, Susan; Rotter, Jerome I; Smith, Lewis J; Soler Artigas, María; Tobin, Martin D; Tsai, Michael Y; Watson, Karol; White, Wendy; Young, Taylor R; Rich, Stephen S; Barr, R Graham

    2014-04-01

    Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema. PMID:23900982

  17. The Effect of Intensified Low Density Lipoprotein Cholesterol Reduction on Recurrent Myocardial Infarction and Cardiovascular Mortality

    PubMed Central

    Huang, Wei-Chun; Lin, Tzu-Wen; Chiou, Kuan-Rau; Cheng, Chin-Chang; Kuo, Feng-Yu; Chiang, Cheng-Hung; Yang, Jin-Shiou; Lin, Ko-Long; Hsiao, Shin-Hung; Yeh, Tong-Chen; Mar, Guang-Yuan; Hsiao, Hsiang-Chiang; Lin, Shoa-Lin; Chiou, Chuen-Wang; Liu, Chun-Peng

    2013-01-01

    Background Lipid-lowering therapy plays an important role in preventing the recurrence of cardiovascular events in patients after acute myocardial infarction (AMI). This study aimed to assess the effect of intensified low density lipoprotein cholesterol (LDL-C) reduction on recurrent myocardial infarction and cardiovascular mortality in patients after AMI. Method The 562 enrolled AMI patients (84.2% male) were divided into two groups according to 3-month LDL-C decrease percentage equal to or more than 40% (n = 165) and less than 40% (n = 397). To evaluate the long-term efficacy of LDL-C reduction, the 5-year outcomes were collected, including time to the first occurrence of myocardial infarction and time to cardiovascular death. Results The baseline characteristics and complication rates were not different between the two study groups. The patients with 3-month LDL-C decrease ≥ 40% had higher baseline LDL-C and lower 3-month, 1-year, 2-year, 3-year, 4-year and 5-year LDL-C than the patients with 3-month LDL-C decrease < 40%. In Kaplan-Meier analyses, those patients with 3-month LDL-C decrease ≥ 40% had a higher rate of freedom from myocardial infarction (p = 0.006) and survival rate (p = 0.02) at 5-year follow-up. The 3-month LDL-C < 40% parameter was significantly related to cardiovascular death (HR: 9.62, 95% CI 1.18-78.62, p < 0.04). Conclusions After acute myocardial infarction, 3-month LDL-C decrease < 40% was identified to be a significant risk factor for predicting 5-year cardiovascular death. The patients with 3-month LDL-C decrease ≥ 40% had a higher rate of freedom from myocardial infarction and lower cardiovascular mortality, even though these patients had higher baseline LDL-C value. PMID:27122737

  18. Increased Free Cholesterol in Plasma Low and Very Low Density Lipoproteins in Non-Insulin-Dependent Diabetes Mellitus: Its Role in the Inhibition of Cholesteryl Ester Transfer

    NASA Astrophysics Data System (ADS)

    Fielding, Christopher J.; Reaven, Gerald M.; Liu, George; Fielding, Phoebe E.

    1984-04-01

    Recombination of low and very low density lipoproteins (VLDL and LDL) from normal subjects with plasma from patients with non-insulin-dependent diabetes mellitus significantly increased the reduced rate of transfer of cholesteryl ester to these lipoproteins, which is characteristic of diabetic plasma, whereas diabetic VLDL and LDL reduced cholesteryl ester transfer rates in normal plasma. VLDL and LDL from diabetic plasma had an increased ratio of free cholesterol to phospholipid compared to normal, and unlike normal VLDL and LDL spontaneously lost free cholesterol to high density lipoprotein. These data suggest that the block to cholesteryl ester transfer to these lipoproteins in non-insulin-dependent diabetes is mediated by their increased free cholesterol content and may be related to the increased risk of these patients for developing atherosclerosis.

  19. Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake.

    PubMed

    Yang, Muhua; Liu, Weidong; Pellicane, Christina; Sahyoun, Christine; Joseph, Biny K; Gallo-Ebert, Christina; Donigan, Melissa; Pandya, Devanshi; Giordano, Caroline; Bata, Adam; Nickels, Joseph T

    2014-02-01

    Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function. PMID:24296663

  20. Effect of nutritional counseling on low-density lipoprotein cholesterol among Thai HIV-infected adults receiving antiretroviral therapy.

    PubMed

    Chotivichien, Saipin; Arab, Lenore; Prasithsirikul, Wisit; Manosuthi, Weerawat; Sinawat, Sangsom; Detels, Roger

    2016-01-01

    HIV-infected patients receiving antiretroviral therapy have increased risk of metabolic syndrome, including dyslipidemia. In this study, we determined whether individual nutritional counseling reduced dyslipidemia, particularly low-density lipoprotein (LDL) cholesterol, among HIV-infected patients with dyslipidemia not currently taking lipid-lowering medication. We conducted a randomized 24-week trial among HIV-infected patients with dyslipidemia who were on antiretroviral therapy and were eligible to initiate therapeutic lifestyle changes according to the Thai National Cholesterol Education Program. Participants were randomly assigned to an intervention group that received individual counseling with a nutritionist for seven sessions (baseline, weeks 2, 4, 8, 12, 18, and 24) and a control group that received standard verbal diet information at baseline and nutritional counseling only at week 24. A 24-h recall technique was used to assess dietary intake for both groups at baseline and week 24. Lipid profile (total cholesterol, LDL, high-density lipoprotein (HDL), and triglyceride) was measured at baseline and after 12 and 24 weeks of therapy. An intention-to-treat and linear mixed model were used. Seventy-two patients were randomly assigned, and 62 (86%) participants completed their lipid profile test. After 12 weeks of follow-up, there were significant reductions in the intervention group for total cholesterol (-14.4 ± 4.6 mg/dL, P = .002), LDL cholesterol (-13.7 ± 4.1 mg/dL, P = .001), and triglyceride (-30.4 ± 13.8 mg/dL, P = .03). A significant reduction in LDL cholesterol was also observed in the control group (-7.7 ± 3.8 mg/dL, P = .04), but there were no significant differences in change of mean lipid levels between the groups at 12 weeks of follow-up. After 24 weeks, participants assigned to the intervention group demonstrated significantly greater decreases in serum total cholesterol (-19.0 ± 4.6 vs. 0.2

  1. [Possibility of New Circulating Atherosclerosis-Related Lipid Markers Measurement in Medical and Complete Medical Checkups: Small Dense Low-Density Lipoprotein Cholesterol and Lipoprotein Lipase].

    PubMed

    Sumino, Hiroyuki; Nakajima, Katsuyuki; Murakami, Masami

    2016-03-01

    Small dense low-density lipoprotein cholesterol (sdLDL-C) concentrations correlate more strongly with cardiovascular disease (CVD) than other LDL-C and large LDL particle concentrations. Lipoprotein lipase (LPL) plays a central role in triglyceride-rich lipoprotein metabolism by catalyzing the hydrolysis of triglycerides in chylomicrons and very low-density lipoprotein particles and is a useful biomarker in diagnosing Type I, Type IV, and Type V hyperlipidemia. Therefore, the measurement of circulating sdLDL-C and LPL concentrations contributes to the assessment of circulating atherosclerosis-related lipid markers. However, the measurement of these lipids has not been fully adopted in medical and complete medical checkups. Recently, novel automated homogenous assay for measuring sdLDL-C and latex particle-enhanced turbidimetric immunoassay (LTIA) for measuring LPL have been developed, respectively. Using these new assays, sdLDL-C values showed excellent agreement with those obtained by isolation of the d = 1.044 - 1.063 g/mL plasma fraction by sequential ultracentrifugation, and LPL values measured with and without heparin injection were highly correlated with the values measured by the LPL-enzyme-linked immunosorbent assay (ELISA). These assays may be superior to the previous assays for the measurement of sdLDL-C and LPL concentrations due their simplicity and reproducibility. The measurements of sdLDL-C and LPL concentrations may be useful as lipid markers in the assessment of the development and progression of atherosclerosis and the detection of pathological conditions and diseases if these markers are measured in medical and complete medical checkups. We have introduced the possibility of the novel measurement of circulating atherosclerosis-related lipid markers such as sdLDL-C and LPL in medical and complete medical checkups. Further studies are needed to clarify whether sdLDL-C and LPL concentrations are related to the development and progression of

  2. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis

    SciTech Connect

    Williams, K.J.; Vallabhajosula, S.; Rahman, I.U.; Donnelly, T.M.; Parker, T.S.; Weinrauch, M.; Goldsmith, S.J.

    1988-01-01

    The metabolism of infused /sup 111/In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t/sub 1/2/) for clearance of /sup 111/In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits. By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue sores. Disappearance of excess plasma cholesterol was > 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative ..gamma.. camera imaging, hepatic trapping of /sup 111/In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance. Aortic uptake of /sup 111/In was < 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, the results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.

  3. Regulation of high density lipoprotein receptors in cultured macrophages: role of acyl-CoA:cholesterol acyltransferase.

    PubMed Central

    Schmitz, G; Niemann, R; Brennhausen, B; Krause, R; Assmann, G

    1985-01-01

    The interaction of human serum high density lipoproteins (HDL) with mouse peritoneal macrophages and human blood monocytes was studied. Saturation curves for binding of apolipoprotein E-free [125I]HDL3 showed at least two components: non-specific binding and specific binding that saturated at approximately 40 micrograms HDL protein/ml. Scatchard analysis of specific binding of apo E-free [125I]-HDL3 to cultured macrophages yielded linear plots indicative of a single class of specific binding sites. Pretreatment of [125I]HDL3 with various apolipoprotein antibodies (anti apo A-I, anti apo A-II, anti apo C-II, anti apo C-III and anti apo E) and preincubation of the cells with anti-idiotype antibodies against apo A-I and apo A-II prior to the HDL binding studies revealed apolipoprotein A-I as the ligand involved in specific binding of HDL. Cellular cholesterol accumulation via incubation with acetylated LDL led to an increase in HDL binding sites as well as an increase in the activity of the cytoplasmic cholesterol esterifying enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Incubation of the cholesterol-loaded cells in the presence of various ACAT inhibitors (Sandoz 58.035, Octimibate-Nattermann, progesterone) revealed a time- and dose-dependent amplification in HDL binding and HDL-mediated cholesterol efflux. It is concluded that the homeostasis of cellular cholesterol in macrophages is regulated in part by the number of HDL binding sites and that ACAT inhibitors enhance HDL-mediated cholesterol efflux from peripheral cells. Images Fig. 4. PMID:2998754

  4. [THE EFFECT OF SATINS: ACTIVATION OF LIPOLYSIS AND ABSORPTION BY INSULIN-DEPENDED CELLS LIPOPROTEINS OF VERY LOW DENSITY, INCREASING OF BIO-AVAILABILITY OF POLYENOIC FATTY ACIDS AND DECREASING OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

    PubMed

    Titov, V N; Malyshev, P P; Amelyushkina, V A; Aripovsky, A V; Smirnov, G P; Polevaya, T Yu; Kabo, S I; Kukhartchuk, V V

    2015-10-01

    The Russian cardiologic R&D production complex of Minzdrav of Russia, 121552 Moscow, Russia The statins are synthetic xenobiotics alien to animal cells. They are unlikely capable to manifest pleiotropic effect. It is feasible to evaluate effect of statins by stages: a) initially a specific inhibition of synthesis of cholesterol alcohol; b) further indirect activation of hydrolysis of triglycerides in lipoproteins of very low density; c) nonspecific activation of cells' receptor absorption of palmitic and oleic lipoproteins of very low density and then d) linoleic and linolenic lipoproteins of low density with all polyenoic fatty acids. On balance, statins activate absorption ofpolyenoic fatty acids by cells. Just they manifest physiological, specific pleiotropic effect. The statins inhibit synthesis of pool of cholesterol alcohol-lipoproteins of very low density condensed between phosphatidylcholines in polar mono-layer phosphatidylcholines+cholesterol alcohol on surface oftriglycerides. The low permeability of mono-layer separates substrate-triglycerides in lipoproteins of very low density and post-heparin lipoprotein lipase in hydrophilic blood plasma. The higher is ratio cholesterol alcohol/phosphatidylcholines in mono-layer of lipoproteins of very low density the slower is lipolysis, formation of ligand lipoproteins of very low density and their absorption by cells under apoB-100-endocytosis. The statins normalize hyperlipemia by force of a) activation of absorption oflipoproteins of very low density by insulin-depended cells and b) activation of absorption of lipoproteins of low density by all cells, increasing of bio-availability of polyenoic fatty acids, activation of apoB-100-endocytosis. The limitation in food of content of palmitic saturated fatty acid and increasing of content of ω-3 polyenoic fatty acids improve "bio-availability" of polyenoic fatty acids and their absorption by cells and also decreases cholesterol alcohol/phosphatidylcholines and

  5. Cholesterol testing and results

    MedlinePlus

    ... lipoprotein (LDL cholesterol) High density lipoprotein (HDL cholesterol) Triglycerides (another type of fat in your blood) Very ... made of fat and protein. They carry cholesterol, triglycerides, and other fats, called lipids, in the blood ...

  6. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis.

    PubMed

    Chasman, Daniel I; Paré, Guillaume; Mora, Samia; Hopewell, Jemma C; Peloso, Gina; Clarke, Robert; Cupples, L Adrienne; Hamsten, Anders; Kathiresan, Sekar; Mälarstig, Anders; Ordovas, José M; Ripatti, Samuli; Parker, Alex N; Miletich, Joseph P; Ridker, Paul M

    2009-11-01

    While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5x10(-8)) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism-including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles-all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay. PMID:19936222

  7. Evidence for low high-density lipoprotein cholesterol levels in Australian indigenous peoples: a systematic review

    PubMed Central

    2014-01-01

    Background Low plasma high-density lipoprotein cholesterol (HDL-C) levels are a strong, independent, but poorly understood risk factor for cardiovascular disease (CVD). Although this atherogenic lipid abnormality has been widely reported in Australia’s Indigenous peoples, Aboriginal and Torres Strait Islanders, the evidence has not come under systematic review. This review therefore examines published data for Indigenous Australians reporting 1) mean HDL-C levels for both sexes and 2) factors associated with low HDL-C. Methods PubMed, Medline and Informit ATSI Health databases were systematically searched between 1950 and 2012 for studies on Indigenous Australians reporting mean HDL-C levels in both sexes. Retrieved studies were evaluated by standard criteria. Low HDL-C was defined as: <1.0 mmol/L. Analyses of primary data associating measures of HDL-C with other CVD risk factors were also performed. Results Fifteen of 93 retrieved studies were identified for inclusion. These provided 58 mean HDL-C levels; 29 for each sex, most obtained in rural/regional (20%) or remote settings (60%) and including 51–1641 participants. For Australian Aborigines, mean HDL-C values ranged between 0.81-1.50 mmol/L in females and 0.76-1.60 mmol/L in males. Two of 15 studies reported HDL-C levels for Torres Strait Islander populations, mean HDL-C: 1.00 or 1.11 mmol/L for females and 1.01 or 1.13 mmol/L for males. Low HDL-C was observed only in rural/regional and remote settings - not in national or urban studies (n = 3) in either gender. Diabetes prevalence, mean/median waist-to-hip ratio and circulating C-reactive protein levels were negatively associated with HDL-C levels (all P < 0.05). Thirty-four per cent of studies reported lower mean HDL-C levels in females than in males. Conclusions Very low mean HDL-C levels are common in Australian Indigenous populations living in rural and remote communities. Inverse associations between HDL-C and central obesity, diabetes

  8. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

    PubMed Central

    Feitosa, Mary F.; Wojczynski, Mary K.; Straka, Robert; Kammerer, Candace M.; Lee, Joseph H.; Kraja, Aldi T.; Christensen, Kaare; Newman, Anne B.; Province, Michael A.; Borecki, Ingrid B.

    2014-01-01

    The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological

  9. Free cholesterol determines reassembled high-density lipoprotein phospholipid phase structure and stability.

    PubMed

    Auton, Matthew; Bassett, G Randall; Gillard, Baiba K; Pownall, Henry J

    2013-06-25

    Reassembled high-density lipoproteins (rHDL) of various sizes and compositions containing apo A-I or apo A-II as their sole protein, dimyristoylphosphatidylcholine (DMPC), and various amounts of free cholesterol (FC) have been isolated and analyzed by differential scanning calorimetry (DSC) and by circular dichroism to determine their stability and the temperature dependence of their helical content. Our data show that the multiple rHDL species obtained at each FC mole percent usually do not have the same FC mole percent as the starting mixture and that the size of the multiple species increases in a quantized way with their respective FC mole percent. DSC studies reveal multiple phases or domains that can be classified as virtual DMPC, which contains a small amount of DMPC that slightly reduces the melting temperature (Tm), a boundary phase that is adjacent to the apo A-I or apo A-II that circumscribes the discoidal rHDL, and a mixed FC/DMPC phase that has a Tm that increases with FC mole percent. Only the large rHDL contain virtual DMPC, whereas all contain boundary phase and various amounts of the mixed FC/DMPC phase according to increasing size and FC mole percent. As reported by others, FC stabilizes the rHDL. For rHDL (apo A-II) compared to rHDL (apo A-I), this occurs in spite of the reduced number of helical regions that mediate binding to the DMPC surface. This effect is attributed to the very high lipophilicity of apo A-II and the reduction in the polarity of the interface between DMPC and the aqueous phase with an increasing FC mole percent, an effect that is expected to increase the strength of the hydrophobic associations with the nonpolar face of the amphipathic helices of apo A-II. These data are relevant to the differential effects of FC and apolipoprotein species on intracellular and plasma membrane nascent HDL assembly and subsequent remodeling by plasma proteins. PMID:23721456

  10. LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes.

    PubMed

    Borrell-Pages, Maria; Carolina Romero, July; Badimon, Lina

    2015-08-01

    Inflammation is triggered after invasion or injury to restore homeostasis. Although the activation of Wnt/β-catenin signaling is one of the first molecular responses to cellular damage, its role in inflammation is still unclear. It was our hypothesis that the low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and the canonical Wnt signaling pathway are modulators of inflammatory mechanisms. Wild-type (WT) and LRP5(-/-) mice were fed a hypercholesterolemic (HC) diet to trigger dislipidemia and chronic inflammation. Diets were supplemented with plant sterol esters (PSEs) to induce LDL cholesterol lowering and the reduction of inflammation. HC WT mice showed increased serum cholesterol levels that correlated with increased Lrp5 and Wnt/β-catenin gene expression while in the HC LRP5(-/-) mice Wnt/β-catenin pathway was shut down. Functionally, HC induced pro-inflammatory gene expression in LRP5(-/-) mice, suggesting an inhibitory role of the Wnt pathway in inflammation. Dietary PSE administration downregulated serum cholesterol levels in WT and LRP5(-/-) mice. Furthermore, in WT mice PSE increased anti-inflammatory genes expression and inhibited Wnt/β-catenin activation. Hepatic gene expression of Vldlr, Lrp2 and Lrp6 was increased after HC feeding in WT mice but not in LRP5(-/-) mice, suggesting a role for these receptors in the clearance of plasmatic lipoproteins. Finally, an antiatherogenic role for LRP5 was demonstrated as HC LRP5(-/-) mice developed larger aortic atherosclerotic lesions than WT mice. Our results show an anti-inflammatory, pro-survival role for LRP5 and the Wnt signaling pathway in peripheral blood leukocytes. PMID:25748163

  11. Effect of ETC-1002 on Serum Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients Receiving Statin Therapy.

    PubMed

    Ballantyne, Christie M; McKenney, James M; MacDougall, Diane E; Margulies, Janice R; Robinson, Paula L; Hanselman, Jeffrey C; Lalwani, Narendra D

    2016-06-15

    ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial (NCT02072161) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220 mg/dl) on stable background statin therapy to 12 weeks of add-on treatment with ETC-1002 120 mg, ETC-1002 180 mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120 mg (-17 ± 4%, p = 0.0055) and ETC-1002 180 mg (-24 ± 4%, p <0.0001) than placebo (-4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non-high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002-treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120 mg or 180 mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile. PMID:27138185

  12. Rice bran oil and oryzanol reduce plasma lipid and lipoprotein cholesterol concentrations and aortic cholesterol ester accumulation to a greater extent than ferulic acid in hypercholesterolemic hamsters.

    PubMed

    Wilson, Thomas A; Nicolosi, Robert J; Woolfrey, Benjamin; Kritchevsky, David

    2007-02-01

    Our laboratory has reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Because RBO has a greater content of the unsaponifiables, which also lower cholesterol compared to most vegetable oils, we wanted to know whether oryzanol or ferulic acid, two major unsaponifiables in RBO, has a greater cholesterol-lowering activity. Forty-eight F(1)B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three per cage) in cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks, at which time they were bled after an overnight fast (16 h) and segregated into 4 groups of 12 with similar plasma cholesterol concentrations. Group 1 (control) continued on the HCD, group 2 was fed the HCD containing 10% RBO in place of coconut oil, group 3 was fed the HCD plus 0.5% ferulic acid and group 4 was fed the HCD plus 0.5% oryzanol for an additional 10 weeks. After 10 weeks on the diets, plasma total cholesterol (TC) and non-high-density lipoprotein cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the RBO (-64% and -70%, respectively), the ferulic acid (-22% and -24%, respectively) and the oryzanol (-70% and -77%, respectively) diets compared to control. Plasma TC and non-HDL-C concentrations were also significantly lower in the RBO (-53% and -61%, respectively) and oryzanol (-61% and -70%, respectively) diets compared to the ferulic acid. Compared to control and ferulic acid, plasma HDL-C concentrations were significantly higher in the RBO (10% and 20%, respectively) and oryzanol (13% and 24%, respectively) diets. The ferulic acid diet had significantly lower plasma HDL-C concentrations compared to the control (-9%). The RBO and oryzanol diets were significantly lower for

  13. Protective effects of sea spaghetti-enriched restructured pork against dietary cholesterol: effects on arylesterase and lipoprotein profile and composition of growing rats.

    PubMed

    Schultz Moreira, Adriana R; Olivero-David, Raúl; Vázquez-Velasco, Miguel; González-Torres, Laura; Benedí, Juana; Bastida, Sara; Sánchez-Muniz, Francisco J

    2014-08-01

    There is a general assumption that seaweeds are hypocholesterolemics and antioxidants. However, controversial results suggest specific properties for each individual alga. This study aims to assess the effect of including Sea Spaghetti alga (S) in a restructured-pork (RP) diet, both enriched and not enriched with dietary cholesterol, on arylesterase (AE) activity and lipoprotein concentration and composition of Wistar rats. Four groups of 10 growing male Wistar rats were each fed a mix of 85% AIN-93M diet and 15% freeze-dried RP for 5 weeks. The control group (C) consumed control RP-C; the S group consumed RP-S with 5% seaweeds; the Chol-C group consumed the C diet but enriched with cholesterol (2.43%) and cholic acid (0.49%); the Chol-S group consumed the S diet but enriched with cholesterol and cholic acid. AE activity was five times higher (P<.01) in S compared with C rats, but three times lower in Chol-S compared with Chol-C rats (P<.01). The Chol-C diet induced hypercholesterolemia but reduced triglycerides (TG), giving rise to the presence of very low-density lipoprotein (VLDL) that was enriched in cholesterol. The Chol-S diet partially blocked (P<.001) the hypercholesterolemic induction of the Chol-C diet, and reduced TG levels (P<.05) with respect to S rats. The cholesterol supplementation increased total cholesterol, VLDL-cholesterol, and intermediate-density lipoprotein+LDL-cholesterol (IDL+LDL)-cholesterol (P<.001) in Chol-C rats, but the effect was lower in the Chol-S diet. In conclusion, RP-S increases the antioxidant capacity within a noncholesterol enriched diet while improving the lipoprotein profile within a cholesterol-enriched diet. PMID:24650072

  14. More Than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

    PubMed Central

    Lane-Donovan, Courtney E.; Philips, Gary T.; Herz, Joachim

    2014-01-01

    Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease pathogenesis and neurodegeneration. This review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction. PMID:25144875

  15. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality.

    PubMed

    Wadhera, Rishi K; Steen, Dylan L; Khan, Irfan; Giugliano, Robert P; Foody, JoAnne M

    2016-01-01

    Cardiovascular (CV) disease is a leading cause of death worldwide, accounting for approximately 31.4% of deaths globally in 2012. It is estimated that, from 1980 to 2000, reduction in total cholesterol accounted for a 33% decrease in coronary heart disease (CHD) deaths in the United States. In other developed countries, similar decreases in CHD deaths (ranging from 19%-46%) have been attributed to reduction in total cholesterol. Low-density lipoprotein cholesterol (LDL-C) has now largely replaced total cholesterol as a risk marker and the primary treatment target for hyperlipidemia. Reduction in LDL-C levels by statin-based therapies has been demonstrated to result in a reduction in the risk of nonfatal CV events and mortality in a continuous and graded manner over a wide range of baseline risk and LDL-C levels. This article provides a review of (1) the relationship between LDL-C and CV risk from a biologic, epidemiologic, and genetic standpoint; (2) evidence-based strategies for LDL-C lowering; (3) lipid-management guidelines; (4) new strategies to further reduce CV risk through LDL-C lowering; and (5) population-level and health-system initiatives aimed at identifying, treating, and lowering lifetime LDL-C exposure. PMID:27206934

  16. Effect of serum, cholesterol and low density lipoprotein on the functionality and structure of lung surfactant films.

    PubMed

    Nahak, Prasant; Nag, Kaushik; Hillier, Ashley; Devraj, Ravi; Thompson, David W; Manna, Kausik; Makino, Kimiko; Ohshima, Hiroyuki; Nakahara, Hiromichi; Shibata, Osamu; Panda, Amiya Kumar

    2014-01-01

    Lung surfactant is a complex mixture of lipid and protein, responsible for alveolar stability, becomes dysfunctional due to alteration of its structure and function by leaked serum materials in disease. Serum proteins, cholesterol and low density lipoprotein (LDL) were studied with bovine lipid extract surfactant (BLES) using Langmuir films, and bilayer dispersions using Raman spectroscopy. While small amount of cholesterol (10 wt%) and LDL did not significantly affect the adsorption and surface tension lowering properties of BLES. However serum lipids, whole serum as well as higher amounts of cholesterol, and LDL dramatically altered the surface properties of BLES films, as well as gel-fluid structures formed in such films observed using atomic force microscopy (AFM). Raman-spectroscopic studies revealed that serum proteins, LDL and excess cholesterol had fluidizing effects on BLES bilayers dispersion, monitored from the changes in hydrocarbon vibrational modes during gel-fluid thermal phase transitions. This study clearly suggests that patho-physiological amounts of serum lipids (and not proteins) significantly alter the molecular arrangement of surfactant in films and bilayers, and can be used to model lung disease. PMID:25409691

  17. Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men.

    PubMed

    Cho, Eo Rin; Jee, Yon Ho; Kim, Sang Won; Sull, Jae Woong

    2016-05-01

    High-density lipoprotein (HDL) cholesterol levels are associated with a decreased risk of coronary artery disease. Several genome-wide association studies that have examined HDL cholesterol levels have implicated myosin light chain 2 regulatory cardiac slow (MYL2) as a possible causal factor. Herein, the association between the rs3782889 single-nucleotide polymorphism (SNP) in the MYL2 gene and HDL cholesterol levels was tested in the Korean population. A total of 4294 individuals were included in a replication study with MYL2 SNP rs3782889. SNP rs3782889 in the MYL2 gene was associated with mean HDL cholesterol level (effect per allele, -1.055 mg dl(-1), P=0.0005). Subjects with the CT/CC genotype had a 1.43-fold (range 1.19-1.73-fold) higher risk of an abnormal HDL cholesterol level (<40 mg dl(-1)) than subjects with the TT genotype. When analyzed by sex, the MYL2 association was stronger in men than that in women. When analyzed by body mass index (BMI), the MYL2 association was much stronger in male subjects with BMI ⩾26.44 kg m(-2) (odds ratio (OR)=2.68; 95% confidence interval (CI)=1.87-3.84; P<0.0001) than that in male subjects with BMI <26.44 kg m(-2). When compared with subjects having the TT genotype and BMI <26.44 kg m(-2), ORs (95% CI) were 3.30 (2.41-4.50) in subjects having the CT/CC genotype and BMI ⩾26.44 kg m(-2) (P for interaction <0.0001). Our results clearly demonstrate that genetic variants in MYL2 influence HDL cholesterol levels in Korean obese male subjects. PMID:26763873

  18. Discordance of Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Particle Versus Cholesterol Concentration for the Prediction of Cardiovascular Disease in Patients With Metabolic Syndrome and Diabetes Mellitus (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

    PubMed

    Tehrani, David M; Zhao, Yanglu; Blaha, Michael J; Mora, Samia; Mackey, Rachel H; Michos, Erin D; Budoff, Matthew J; Cromwell, William; Otvos, James D; Rosenblit, Paul D; Wong, Nathan D

    2016-06-15

    A stronger association for low-density lipoprotein particle (LDL-P) and high-density lipoprotein particle (HDL-P) versus cholesterol concentrations (LDL-C and HDL-C) in predicting coronary heart disease (CHD) has been noted. We evaluate the role of these factors and extent of particle-cholesterol discordance in those with diabetes mellitus (DM) and metabolic syndrome (MetS) for event prediction. In the Multi-Ethnic Study of Atherosclerosis, we examined discordance of LDL and HDL (defined as a subject's difference between baseline particle and cholesterol percentiles), LDL-C, LDL-P, HDL-C, and HDL-P in relation to incident CHD and cardiovascular disease (CVD) events in subjects with DM, MetS (without DM), or neither condition using Cox regression. Of the 6,417 subjects with 10-year follow-up, those with MetS (n = 1,596) and DM (n = 838) had significantly greater LDL and HDL discordance compared with those without these conditions. In discordance models, only LDL discordance (per SD) within the MetS group was positively associated with CHD events (adjusted hazard ratio [HR] = 1.22, 95% confidence interval [CI] 1.01 to 1.48, p <0.05). In models with individual particle/cholesterol variables (per SD), within the DM group, HDL-P was inversely (HR 0.71, 95% CI 0.52 to 0.96, p <0.05) and LDL-C positively (HR 1.47, 95% CI 1.07 to 2.03, p <0.05) associated with CHD. In those with MetS, only LDL-P was positively associated with CHD (HR 1.34, 95% CI 1.00 to 1.78, p <0.05). Similar findings were also seen for CVD. LDL discordance and higher LDL-P in MetS, and higher LDL-C and lower HDL-P in DM, predict CHD and CVD, supporting a potential role for examining lipoprotein particles and discordances in those with MetS and DM. PMID:27156827

  19. [THE SPIRIT CHOLESTEROL, BIOLOGICA L ROLE AT STAGES OF PHYLOGENESIS, MECHANISMS OF INHIBITION OF SYNTHESIS OF STEROL BY STATINS, FACTORS OF PHARMACOGENOMICS AND DIAGNOSTIC SIGNIFICANCE OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

    PubMed

    Titov, V N; Kotlovskii, M Yu; Pokrovskii, A A; Kotlovskaia, O S; Osedko, A V; Titova, N M; Kotlovskii, Yu V; Digaii, A M

    2015-04-01

    The hypolipidemic effect of statins is realized by inhibition of synthesis of local pool of cholesterol spirit in endoplasmic net of hepatocytes. The cholesterol spirit covers all hydrophobic medium of triglycerides with polar mono layer of phosphatidylcholines and cholesterol spirit prior to secretion of lipoproteins of very low density into hydrophilic medium. The lesser mono layer between lipase enzyme and triglycerides substrate contains of cholesterol spirit the higher are the parameters of hydrolysis of palmitic and oleic lipoproteins of very low density. The sequence of effect of statins is as follows: blocking of synthesis in hepatocytes and decreasing of content of unesterified cholesterol spirit in blood plasma; activation of hydrolysis of triglycerides in palmitic and oleic lipoproteins of very low density; formation of ligand lipoproteins of very low density and their absorption by cells by force of apoB-100 endocytosis; decreasing in blood of content of polyenoic fatty acids, equimolar esterified by cholesterol spirit, polyethers of cholesterol spirit and decreasing of level of cholesterol spirit-lipoproteins of very low density. There is no way to eliminate aphysiological effect of disordered biological function of trophology (nutrition) on metabolism of fatty acids in population by means of pharmaceuticals intake. It is necessary to eliminate aphysiological effect of environment. To decrease rate of diseases of cardiovascular system one has to decrease in food content of saturated fatty acids and in the first instance palmitic saturated fatty acid, trans-form fatty acid, palmitoleic fatty acids up to physiological values and increase to the same degree the content of polyenoic fatty acids. The saturated fatty acids block absorption of polyenoic fatty acids by cells. The atherosclerosis is a deficiency of polyenoic fatty acids under surplus of palmitic saturated fatty acid. PMID:26189285

  20. Lipoprotein cholesterol and triglyceride concentrations associated with dog body condition score; effect of recommended fasting duration on sample concentrations in Japanese private clinics

    PubMed Central

    USUI, Shiho; YASUDA, Hidemi; KOKETSU, Yuzo

    2015-01-01

    The objectives of this study were to survey clinics’ guidance about recommended fasting duration (FD) prior to lipoprotein analysis, and to characterize lipoprotein cholesterol and triglyceride concentrations in obese and overweight dogs categorized on the basis of the 5-point body condition score (BCS) scale. A dataset was created from lipoprotein analysis medical records of 1,538 dogs from 75 breeds in 354 clinics from 2012 to 2013. A phone survey was conducted to obtain the clinics’ FD. Two-level linear mixed-effects models were applied to the data. Over 50% of the clinics said they recommended fasting for 12 hr or more. Dogs in clinics with FD 12 hr or more had lower chylomicron triglyceride concentrations than those in clinics with FD less than 8 hr (P=0.05). Mean (± SEM) BCS at sampling was 3.7 ± 0.02. Obese and overweight dogs had higher very low density lipoprotein (VLDL) and high density lipoprotein (HDL) cholesterol and triglyceride concentrations than ideal dogs (P<0.05), but no such difference was found for low density lipoprotein cholesterol and triglyceride concentrations (P≥0.07). Across all BCS, as dog age rose from 0 to 8 years old, HDL cholesterol concentrations decreased by 13.5 mg/dl, whereas VLDL triglyceride concentrations increased by 81.7 mg/dl (P<0.05). In conclusion, FD of 8 hr or less may affect lipoprotein lipid concentrations. Obese and overweight dogs were characterized as having high VLDL and HDL cholesterol and triglyceride concentrations. PMID:25866404

  1. Predictive value of lipoprotein indices for residual risk of acute myocardial infarction and sudden death in men with low-density lipoprotein cholesterol levels <120 mg/dl.

    PubMed

    Tanaka, Fumitaka; Makita, Shinji; Onoda, Toshiyuki; Tanno, Kozo; Ohsawa, Masaki; Itai, Kazuyoshi; Sakata, Kiyomi; Omama, Shin-Ichi; Yoshida, Yuki; Ogasawara, Kuniaki; Ogawa, Akira; Ishibashi, Yasuhiro; Kuribayashi, Toru; Okayama, Akira; Nakamura, Motoyuki

    2013-10-15

    Several epidemiologic studies have demonstrated that plasma low-density lipoprotein cholesterol (LDL-C) profile is a key risk indicator for coronary heart disease (CHD). However, almost half of all patients with CHD have normal LDL-C levels. A total of 7,931 male subjects aged ≥40 years from the general population with no cardiovascular history and no use of lipid-lowering agents were followed for incidence of acute myocardial infarction (AMI) and sudden death. Of the 4,827 participants with LDL-C levels <120 mg/dl, 55 subjects had a first AMI/sudden death during an average of 5.5 years of follow-up. After adjustment for confounding factors, multiadjusted hazard ratios (HRs) were increased by 1 SD for non-high-density lipoprotein cholesterol (non-HDL-C; HR = 1.36, 95% confidence interval [CI], 1.02 to 1.81), total cholesterol (TC)/HDL-C ratio (HR = 1.40, 95% CI: 1.11 to 1.78) and LDL-C/HDL-C ratio (HR = 1.32, 95% CI: 1.02 to 1.73) but not for LDL-C (HR = 1.09, 95% CI: 0.82 to 1.44) and HDL-C (HR = 0.84, 95% CI: 0.68 to 1.04). When stratified as categorical variables on the basis of points with highest accuracy on receiver operating characteristic analysis, non-HDL-C levels >126 mg/dl (HR = 1.25, 95% CI: 1.03 to 1.51), TC/HDL-C ratio above 3.5 (HR = 1.22, 95% CI: 1.01 to 1.48) and LDL-C/HDL-C ratio >1.9 (HR = 1.25, 95% CI: 1.04 to 1.51) had increased multiadjusted HRs for AMI/sudden death. In conclusion, in men with LDL-C levels <120 mg/dl, non HDL-C, TC/HDL-C, and LDL-C/HDL-C ratios have predictive value for residual risk of AMI/sudden death. PMID:23831165

  2. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.

    PubMed Central

    Williams, K J; Vallabhajosula, S; Rahman, I U; Donnelly, T M; Parker, T S; Weinrauch, M; Goldsmith, S J

    1988-01-01

    The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t1/2) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits (means +/- SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was greater than 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative gamma camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% +/- 1.7% (WHHL) and 16.8% +/- 1.0% (normal of total 111In. Aortic uptake of 111In was less than 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia. PMID:3422421

  3. Streptococcal serum opacity factor increases the rate of hepatocyte uptake of human plasma high-density lipoprotein cholesterol.

    PubMed

    Gillard, Baiba K; Rosales, Corina; Pillai, Biju K; Lin, Hu Yu; Courtney, Harry S; Pownall, Henry J

    2010-11-16

    Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high-density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM) that contains the cholesterol esters (CE) of up to ∼400000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins, and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E-dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. The uptake of [(3)H]CE by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was 2.4 and 4.5 times faster, respectively, than from control HDL. CERM-[(3)H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[(3)H]CE uptake by both receptors. RAP and heparin inhibit CERM-[(3)H]CE but not HDL-[(3)H]CE uptake, thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases the rate of CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase the level of hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789

  4. Apolipoprotein B100 secretion by cultured ARPE-19 cells is modulated by alteration of cholesterol levels.

    PubMed

    Wu, Tinghuai; Fujihara, Masashi; Tian, Jane; Jovanovic, Miroslava; Grayson, Celene; Cano, Marisol; Gehlbach, Peter; Margaron, Philippe; Handa, James T

    2010-09-01

    Cholesteryl ester rich apolipoprotein B100 (apoB100) lipoproteins accumulate in Bruch's membrane before the development of age-related macular degeneration. It is not known if these lipoproteins come from the circulation or local ocular tissue. Emerging, but incomplete evidence suggests that the retinal pigmented epithelium (RPE) can secrete lipoproteins. The purpose of this investigation was to determine (i) whether human RPE cells synthesize and secrete apoB100, and (ii) whether this secretion is driven by cellular cholesterol, and if so, (iii) whether statins inhibit this response. The established, human derived ARPE-19 cells challenged with 0-0.8 mM oleic acid accumulated cellular cholesterol, but not triglycerides. Oleic acid increased the amount of apoB100 protein recovered from the medium by both western blot analysis and (35) S-radiolabeled immunoprecipitation while negative stain electron microscopy showed lipoprotein-like particles. Of nine statins evaluated, lipophilic statins induced HMG-CoA reductase mRNA expression the most. The lipophilic Cerivastatin (5 μM) reduced cellular cholesterol by 39% and abrogated apoB100 secretion by 3-fold. In contrast, the hydrophilic statin Pravastatin had minimal effect on apoB100 secretion. These data suggest that ARPE-19 cells synthesize and secrete apoB100 lipoproteins, that this secretion is driven by cellular cholesterol, and that statins can inhibit apoB100 secretion by reducing cellular cholesterol. PMID:20598021

  5. Add-on rosiglitazone therapy improves plasminogen activity and high-density lipoprotein cholesterol in type 2 diabetes mellitus.

    PubMed

    Mustaffa, Nazri; Ibrahim, Suhairi; Abdullah, Wan Zaidah; Yusof, Zurkurnai

    2011-09-01

    Rosiglitazone is an oral hypoglycaemic agent of the thiazolidinedione group. This study aimed to assess changes in the diabetic prothrombotic state via plasminogen activity and changes in surrogate markers of atherosclerotic burden via ankle-brachial pressure index (ABPI) measurements after rosiglitazone was added to a pre-existing type 2 diabetes mellitus treatment regime. A nonblinded interventional study was designed. Fifty-nine patients were enrolled. Rosiglitazone-naïve patients were prescribed oral rosiglitazone 4 mg daily for 10 weeks. ABPI, plasminogen activity, glycosylated haemoglobin (HbA1c) and fasting lipid profile were measured pretreatment and post-treatment. Forty-eight patients completed the study. At the end of this study, mean plasminogen activity improvement was nearly 16% (P<0.05), mean ABPI improvement was 0.01 (P=0.439), mean HbA1c reduction was 0.51% (P<0.05), mean total cholesterol (TC) increase was 0.36 mmol/l (P<0.05), mean high-density lipoprotein cholesterol (HDL-C) increase was 0.15 mmol/l (P<0.05) and mean low-density lipoprotein cholesterol increased by 0.19 mmol/l (P=0.098). Rosiglitazone significantly improved plasminogen activity. There was also significant HbA1c reduction, and rise in both TC and HDL-C. Thus, rosiglitazone potentially improves the atherosclerotic burden and prothrombotic state. In future, more studies are needed to confirm the relationship between rosiglitazone, fibrinolytic system and atheromatous reduction in type 2 diabetes mellitus. PMID:21537159

  6. The effect of 17 beta-estradiol on cholesterol in human macrophages is influenced by the lipoprotein milieu

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogen and testosterone are thought to modulate coronary heart disease (CHD) risk. To examine how these hormones affect human macrophage cholesterol transport, a key factor in atherogenesis, we obtained monocytes from healthy male and postmenopausal female donors (age 50-70 y). Cells were allowe...

  7. Rice bran proteins and their hydrolysates modulate cholesterol metabolism in mice on hypercholesterolemic diets.

    PubMed

    Zhang, Huijuan; Wang, Jing; Liu, Yingli; Gong, Lingxiao; Sun, Baoguo

    2016-06-15

    The hypolipidemic properties of defatted rice bran protein (DRBP), fresh rice bran protein (FRBP), DRBP hydrolysates (DRBPH), and FRBP hydrolysates (FRBPH) were determined in mice on high fat diets for four weeks. Very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C) contents, and the hepatic total cholesterol content were reduced while fecal total cholesterol and total bile acid (TBA) contents were increased in the FRBPH diet group. The expression levels of hepatic genes for cholesterol biosynthesis HMG-CoAR and SREBP-2 were lowest in the FRBPH diet group. The mRNA level of HMG-CoAR was significantly positively correlated with the hepatic TG content (r = 0.82, P < 0.05). The mRNA levels of genes related to bile acid biosynthesis and cholesterol efflux, CYP7A1, ABCA1, and PPARγ were up-regulated in all test groups. The results suggest that FRBPH regulates cholesterol metabolism in mice fed the high fat and cholesterol diet by increasing fecal steroid excretion and expression levels of genes related to bile acid synthesis and cholesterol efflux, and the down-regulation of the expression levels of genes related to cholesterol biosynthesis. PMID:27216972

  8. Soy milk powder supplemented with phytosterol esters reduced serum cholesterol level in hypercholesterolemia independently of lipoprotein E genotype: a random clinical placebo-controlled trial.

    PubMed

    Dong, Shan; Zhang, Ran; Ji, Ya-Cheng; Hao, Jia-Yin; Ma, Wei-Wei; Chen, Xu-Dong; Xiao, Rong; Yu, Huan-Ling

    2016-08-01

    Phytosterols (PSs) are reported to lower the serum total cholesterol and low-density lipoprotein cholesterol concentrations enriched in some fatty foods, such as margarine. However, these high-fat foods are not very suitable for older people. Soy milk is the favorite food for elderly people in China; therefore, we hypothesized that the consumption of soy milk powder supplemented with PSs would decrease the serum cholesterol levels in older Chinese people independent of the genotypes of apolipoprotein E (ApoE). Mild to moderate hyperlipidemic patients (n = 170) were recruited from different communities and treated with placebo soy milk powder or 3.4 g PS esters-enriched soy milk powder (2.0 g/d free PS in 30 g soy milk powder). The fasting serum lipid profiles at the baseline and after 3 and 6 months of intervention were measured. The ApoE genotype was also determined. After 3 months of PS intervention, the serum lipid profile was not changed significantly in either group. The serum total cholesterol, low-density lipoprotein cholesterol, and non- high-density lipoprotein cholesterol levels decreased by 9.3%, 11.4%, and 12.6%, respectively, in the PS group at the end of the intervention (6 months) compared with the control group, whereas the serum high-density lipoprotein cholesterol and triglyceride levels were not affected significantly. In the PS group, both the ApoE3 and ApoE4 carriers had a similar response to PS consumption. These findings suggested that PS-fortified soy milk powder was effective in lowering the serum cholesterol levels in older Chinese volunteers with mild to moderate hypercholesterolemia in both the ApoE3 and ApoE4 carriers. PMID:27440543

  9. Interaction of high-density and low-density lipoproteins to solid surfaces coated with cholesterol as determined by an optical fiber-based biosensor

    NASA Astrophysics Data System (ADS)

    Singh, Bal R.; Poirier, Michelle A.

    1993-05-01

    In recent years, the use of fiber optics has become an important tool in biomedicine and biotechnology. We are involved in developing and employing a new system which, through the use of fiber optics, may be capable of measuring the content of cholesterol and lipoproteins in blood samples in real time. In the optical fiber-based biosensor, a laser beam having a wavelength of 512 nm (green light) is launched into an optical fiber, which transmits the light to its distal end. An evanescent wave (travelling just outside the fiber core) is used to excite rhodamine-labelled HDL or LDL which become bound to the fiber or to fiber-bound molecules. The fluorescence (red light) is coupled back into the fiber and detected with a photodiode. Preliminary work has involved testing of high density lipoprotein (HDL) binding to a cholesterol-coated fiber and to a bare fiber and low density lipoprotein (LDL) binding to a cholesterol-coated fiber. A significant difference was observed in the binding rate of HDL (5 (mu) g/mL and lower) to a bare fiber as opposed to a cholesterol-coated fiber. The binding rate of HDL (5 (mu) g/mL) to a bare fiber was 7.5 (mu) V/sec and to a cholesterol-coated fiber was 3.5 (mu) V/sec. We have calculated the binding affinity of LDL to a cholesterol- coated fiber as 1.4 (mu) M-1. These preliminary results suggest that the optical fiber-based biosensor can provide a unique and promising approach to the analysis of lipoprotein interaction with solid surfaces and with cholesterol. More importantly, the results suggest that this technique may be used to assess the binding of blood proteins to artificial organs/tissues, and to measure the amount of cholesterol, HDL and LDL in less than a minute.

  10. [The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy].

    PubMed

    Dobiásová, M; Frohlich, J

    2000-03-01

    The new atherogenic plasma index (AIP) is a logarithmic transformation of the ratio of the molar triglyceride (TG) concentration and high density lipoprotein cholesterol (HDL-C). AIP correlates closely with the size of LDL particles (r = 0.8) and esterification rate of plasma cholesterol devoid of apo B lipoproteins (FERHDL), r = 0.9 which are considered at present the most sensitive indicators of the atherogenic plasma profile. AIP was recommended by the authors, based on analysis of results of 11 previous studies (1156 subjects) where FERHDL and plasma lipid parameters were investigated in different groups of people who differed as to the atherogenic risk. The AIP index was moreover used for evaluation of a clinical study comprising 609 patients with hyperlipidaemia, who were treated for three months with ciprofibrate (Lipanor). The mean AIP values of non-risk groups (plasma from umbilical blood, children, healthy women etc.) equalled zero or were lower, while with an increasing atherogenic risk (men, women after the menopause) AIP reached positive values, incl. high positive values in risk groups (plasma of diabetic subjects, patients with HLP, patients with positive angiography, myocardial infarction etc.). In all groups women had lower AIP values as compared with males. In patients after Lipanor therapy the AIP declined (from 0.58 +/- 0.17 to 0.33_0.18 in men, from 0.50 +/- 0.18 to 0.21 +/- 0.19 in women). If we consider AIP values from negative ones to 0.15 as "safe" from the aspect of atherogenicity, before Lipanor treatment these "safe" levels were recorded in 1.5% men and in 5.2% women and after treatment in 32% men and 48% women. The results indicate, that AIP which reflects the plasma lipoprotein profile quantifies the relations between TG and HDL-C and thus can be an objective indicator of the atherogenic risk and effectiveness of treatment and it is useful because it can be assessed in any surgery. PMID:11048517

  11. Frequency of Attainment of Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol Goals in Cardiovascular Clinical Practice (from the National Cardiovascular Data Registry PINNACLE Registry).

    PubMed

    Spinler, Sarah A; Cziraky, Mark J; Willey, Vincent J; Tang, Fengming; Maddox, Thomas M; Thomas, Tyan; Dueñas, Gladys G; Virani, Salim S

    2015-08-15

    Studies have found that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior marker for coronary heart disease compared to low-density lipoprotein cholesterol (LDL-C). Little is known about achievement of non-HDL-C goals outside clinical trials. Within a population of 146,064 patients with dyslipidemia in the PINNACLE Registry and a subgroup of 36,188 patients with diabetes mellitus (DM), we examined the proportion of patients and patient characteristics associated with having LDL-C, non-HDL-C, and both LDL-C and non-HDL-C levels at National Cholesterol Education Program goals. LDL-C, non-HDL-C, and both LDL-C and non-HDL-C goals in the overall cohort were achieved by 73%, 73.4%, and 68.9% patients, respectively. Significant predictors of meeting all 3 goals were age, male gender, statin, nonstatin, and combined statin plus nonstatin use. Patients with co-morbidities of hypertension, previous stroke or transient ischemic attack, peripheral arterial disease, myocardial infarction, and smoking were less likely to have LDL-C, non-HDL-C, and both LDL-C and non-HDL-C levels at National Cholesterol Education Program goal. In the overall cohort, patients with DM were less likely to meet non-HDL-C and both LDL-C and non-HDL-C goals. In the subgroup of patients with DM, predictors of meeting lipid goals were similar to the overall cohort. In conclusion, these data suggest contemporary treatment patterns by cardiologists successfully achieve lipid goals in most patients. Younger, female patients and those with atherosclerotic cardiovascular disease and risk factors, such as hypertension and DM, are less likely to achieve goals and may require more careful follow-up after statin initiation. Both LDL-C and non-HDL-C goals are achieved in <70% of patients, suggesting room for improvement if a goal-targeted individualized strategy is adopted. PMID:26089010

  12. Synthetic High-Density Lipoprotein-Like Nanocarrier Improved Cellular Transport of Lysosomal Cholesterol in Human Sterol Carrier Protein-Deficient Fibroblasts.

    PubMed

    Nam, Da-Eun; Kim, Ok-Kyung; Park, Yoo Kyoung; Lee, Jeongmin

    2016-01-01

    Sterol carrier protein-2 (SCP-2), which is not found in tissues of people with Zellweger syndrome, facilitates the movement of cholesterol within cells, resulting in abnormal accumulation of cholesterol in SCP-2-deficient cells. This study investigated whether synthetic high-density lipoprotein-like nanocarrier (sHDL-NC) improves the cellular transport of lysosomal cholesterol to plasma membrane in SCP-2-deficient fibroblasts. Human SCP-2-deficient fibroblasts were incubated with [(3)H-cholesterol]LDL as a source of cholesterol and sHDL-NC. The cells were fractionated by centrifugation permit tracking of [(3)H]-cholesterol from lysosome into plasma membrane. Furthermore, cellular content of cholesteryl ester as a storage form and mRNA expression of low-density lipoprotein (LDL) receptor were measured to support the cholesterol transport to plasma membrane. Incubation with sHDL-NC for 8 h significantly increased uptake of [(3)H]-cholesterol to lysosome by 53% and further enhanced the transport of [(3)H]-cholesterol to plasma membrane by 32%. Treatment with sHDL-NC significantly reduced cellular content of cholesteryl ester and increased mRNA expression of LDL receptor (LDL-R). In conclusion, sHDL-NC enables increased transport of lysosomal cholesterol to plasma membrane. In addition, these data were indirectly supported by decreased cellular content of cholesteryl ester and increased gene expression of LDL-R. Therefore, sHDL-NC may be a useful vehicle for transporting cholesterol, which may help to prevent accumulation of cholesterol in SCP-2-deficient fibroblasts. PMID:26684407

  13. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV.

    PubMed

    Goldberg, I J; Scheraldi, C A; Yacoub, L K; Saxena, U; Bisgaier, C L

    1990-03-15

    Lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides (TG) contained in chylomicrons requires the presence of a cofactor, apolipoprotein (apo) C-II. The physiological mechanism by which chylomicrons gain apoC-II necessary for LPL activation in whole plasma is not known. Using a gum arabic stabilized TG emulsion, activation of LPL by lipoprotein apoC-II was studied. Hydrolysis of TG by LPL was greater in the presence of serum than with addition of either high density lipoproteins (HDL) or very low density lipoproteins (VLDL). LPL activation by either VLDL or HDL increased with addition of the lipoprotein-free fraction of plasma. A similar increase in LPL activity by addition of the lipoprotein-free fraction together with HDL or VLDL was observed when another TG emulsion (Intralipid) or TG-rich lipoproteins from an apoC-II deficient subject were used as a substrate. Human apoA-IV, apoA-I, apoE, and cholesteryl ester transfer protein were assessed for their ability to increase LPL activity in the presence of VLDL. At and below physiological concentrations, only apoA-IV increased LPL activity. One hundred percent of LPL activity measured in the presence of serum was achieved using VLDL plus apoA-IV. In the absence of an apoC-II source, apoA-IV had no effect on LPL activity. Removal of greater than 80% of the apoA-IV from the nonlipoprotein-containing fraction of plasma by incubation with Intralipid markedly reduced its ability to activate LPL in the presence of VLDL or HDL. Gel filtration chromatography demonstrated that incubation of the nonlipoprotein-containing fraction of plasma with HDL and the TG emulsion caused increased transfer of apoC-II to the emulsion and association of apoA-IV with HDL. Our studies demonstrate that apoA-IV increases LPL activation in the presence of lipoproteins. We hypothesize that apoA-IV is required for efficient release of apoC-II from either HDL or VLDL, which then allows for LPL-mediated hydrolysis of TG in nascent

  14. High-density lipoprotein cholesterol esterification and transfer rates to lighter density lipoproteins mediated by cholesteryl ester transfer protein in the fasting and postprandial periods are not altered in type 1 diabetes mellitus.

    PubMed

    Medina; Nunes; Carrilho; Shimabukuru; Lottenberg; Lottenberg; McPherson; Krauss; Quintão

    2000-10-01

    Background: Diabetes mellitus is associated with atherosclerosis that has, in part, been ascribed to abnormalities in the reverse cholesterol transport system. Methods: We determined, in the fasting and post-alimentary periods, rates of HDL cholesterol esterification and transfer to apoB-containing lipoproteins, cholesteryl ester transfer protein (CETP) concentration, and apoB lipoprotein size in 10 type 1 diabetics and 10 well-matched controls. Autologous HDL was labeled with [14C]cholesterol and incubated at 37 degrees C during a period of 30 min for measurement of the cholesterol esterification rate (CER), as well as for 24 h for measurement of the endogenous HDL [14C]cholesteryl ester ([14C]CE) transfer rate to apoB-containing lipoproteins after 2- and 4-h incubations with the subject's own plasma. Exogenous cholesteryl ester transfer activity (CETA) was estimated by incubation of the participant's plasma (CETP source) with [14C]CE-HDL and VLDL from a pool of plasma donors. ApoB lipoprotein size was determined using non-denaturing polyacrylamide gradient gel electrophoresis of whole plasma. Results: Contrary to previous studies, we showed that even not well-controlled type 1 diabetics did not differ from lipid-matched, non-diabetic subjects in HDL-[14C]cholesterol esterification rate, transfer rates, or CETP concentration. CETP concentration correlates with the exogenous method of [14C]CE transfer and with the endogenous method only when the latter is corrected for plasma triacylglycerol (TG) concentration. In addition, during the postprandial phase, diabetic patients' VLDL are smaller and IDL size increases less than in controls. Conclusion: In type 1 diabetes mellitus, CETA is not altered when the plasma levels of donor and/or acceptor lipoproteins are within the normal range. PMID:11025251

  15. Primary Low Level of High-Density Lipoprotein Cholesterol and Risks of Coronary Heart Disease, Cardiovascular Disease, and Death: Results From the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Ahmed, Haitham M; Miller, Michael; Nasir, Khurram; McEvoy, John W; Herrington, David; Blumenthal, Roger S; Blaha, Michael J

    2016-05-15

    Prior studies observing associations between low levels of high-density lipoprotein (HDL) cholesterol and cardiovascular disease (CVD) have often been conducted among persons with metabolic or other lipid abnormalities. In this study, we investigated the association between primary low HDL cholesterol and coronary heart disease (CHD), CVD, and all-cause death after adjustment for confounders in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants who were free of clinical CVD were recruited from 6 US research centers from 2000 to 2002 and followed for a median duration of 10.2 years. We defined "primary low HDL cholesterol" as HDL cholesterol level <40 mg/dL (men) or <50 mg/dL (women), triglyceride level <100 mg/dL, and low-density lipoprotein cholesterol level <100 mg/dL (n = 158). We defined an "optimal" lipid profile as HDL cholesterol ≥40 mg/dL (men) or ≥50 mg/dL (women) and triglycerides and low-density lipoprotein cholesterol <100 mg/dL (n = 780). For participants with primary low HDL cholesterol versus those with an optimal lipid profile, adjusted hazard ratios for total CHD, CVD, and death were 2.25 (95% confidence interval (CI): 1.20, 4.21; P = 0.011), 1.93 (95% CI: 1.11, 3.34; P = 0.020), and 1.11 (95% CI: 0.67, 1.84; P = 0.69), respectively. Participants with primary low HDL cholesterol had higher risks of CHD and CVD than participants with optimal lipid profiles but no difference in survival after a median 10.2 years of follow-up. PMID:27189327

  16. Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleot...

  17. Effects of a 12-week healthy-life exercise program on oxidized low-density lipoprotein cholesterol and carotid intima-media thickness in obese elderly women

    PubMed Central

    Park, Jong-Hwan; Park, Hyuntae; Lim, Seung-Taek; Park, Jin-Kee

    2015-01-01

    [Purpose] This study examined the effects of a 12-week exercise program on plasma level of oxidized low-density lipoprotein cholesterol in obese elderly women, who are at increased risk of heart disease morbidity. [Subjects and Methods] Twenty participants were assigned into either a control (n = 10) or a supervised exercise program (n = 10) group. The 12-week exercise intervention was performed 3 days per week and involved combined aerobic exercise, resistance exercise, and traditional Korean dance. [Results] Two-factor analysis of variance revealed significant group × time interactions for body mass, diastolic blood pressure, appendicular muscle mass. For high-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and the ratio of oxidized low-/high-density lipoprotein cholesterol, two-factor analysis of variance revealed significant interactions (group × time), indicating responses differed significantly between the control and exercise groups after 12 weeks. [Conclusion] A 12-week low- to moderate-intensity exercise program appears to be beneficial for obese elderly women by improving risk factors for cardiovascular disease. PMID:26157235

  18. The Effect of Aerobic Exercise on Total Cholesterol, High-Density Lipoprotein, Apolipoprotein B, Apolipoprotein A-I, and Percent Body Fat in Adolescent Females.

    ERIC Educational Resources Information Center

    Lungo, Diane; And Others

    The effect of aerobic exercise on total cholesterol (TC), high-density lipoprotein (HDL), apolipoprotein B (Apo B), apolioprotein A-I (Apo A-I), and percent body fat in adolescent females was studied. The control subjects (n=86) were volunteers who had completed a physical education class at least six months prior to the commencement of the study,…

  19. Effects of a 12-week healthy-life exercise program on oxidized low-density lipoprotein cholesterol and carotid intima-media thickness in obese elderly women.

    PubMed

    Park, Jong-Hwan; Park, Hyuntae; Lim, Seung-Taek; Park, Jin-Kee

    2015-05-01

    [Purpose] This study examined the effects of a 12-week exercise program on plasma level of oxidized low-density lipoprotein cholesterol in obese elderly women, who are at increased risk of heart disease morbidity. [Subjects and Methods] Twenty participants were assigned into either a control (n = 10) or a supervised exercise program (n = 10) group. The 12-week exercise intervention was performed 3 days per week and involved combined aerobic exercise, resistance exercise, and traditional Korean dance. [Results] Two-factor analysis of variance revealed significant group × time interactions for body mass, diastolic blood pressure, appendicular muscle mass. For high-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and the ratio of oxidized low-/high-density lipoprotein cholesterol, two-factor analysis of variance revealed significant interactions (group × time), indicating responses differed significantly between the control and exercise groups after 12 weeks. [Conclusion] A 12-week low- to moderate-intensity exercise program appears to be beneficial for obese elderly women by improving risk factors for cardiovascular disease. PMID:26157235

  20. A predictor of atheroma progression in patients achieving very low levels of low-density lipoprotein cholesterol

    PubMed Central

    Nozue, Tsuyoshi; Yamamoto, Shingo; Tohyama, Shinichi; Fukui, Kazuki; Umezawa, Shigeo; Onishi, Yuko; Kunishima, Tomoyuki; Hibi, Kiyoshi; Terashima, Mitsuyasu; Michishita, Ichiro

    2013-01-01

    An aggressive reduction in low-density lipoprotein cholesterol (LDL-C) with statins produces regression or stabilization of coronary artery plaques. However, after achieving very low levels of LDL-C, atheroma regression is not observed in all patients. The purpose of the present study was to evaluate the determinants of atheroma progression despite achieving very low levels of LDL-C. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound in the TRUTH study. Of these, 33 patients who achieved an on-treatment LDL-C level of <70 mg/dl were divided into 2 groups according to increase in plaque volume (progressors, n= 16) or decrease in plaque volume (regressors, n= 17) during an 8-month follow-up period. At the 8-month follow-up, serum LDL-C and apolipoprotein B levels were significantly lower in progressors than in regressors; however, significant increases in high-density lipoprotein cholesterol and apolipoprotein AI and decreases in high-sensitivity C-reactive protein and oxidized LDL were observed only in regressors. The changes in the n-3 to n-6 polyunsaturated fatty acid ratios significantly differed between the 2 groups. Multivariate regression analysis showed that a decrease in the eicosapentaenoic acid + docosahexaenoic acid/arachidonic acid ratio was a significant predictor associated with atheroma progression (β= -0.512, p= 0.004). In conclusions, n-3 to n-6 polyunsaturated fatty acid ratios affected coronary artery plaque progression and regression in patients who achieved very low levels of LDL-C during statin therapy. PMID:24224137

  1. A predictor of atheroma progression in patients achieving very low levels of low-density lipoprotein cholesterol.

    PubMed

    Nozue, Tsuyoshi; Yamamoto, Shingo; Tohyama, Shinichi; Fukui, Kazuki; Umezawa, Shigeo; Onishi, Yuko; Kunishima, Tomoyuki; Hibi, Kiyoshi; Terashima, Mitsuyasu; Michishita, Ichiro

    2013-01-01

    An aggressive reduction in low-density lipoprotein cholesterol (LDL-C) with statins produces regression or stabilization of coronary artery plaques. However, after achieving very low levels of LDL-C, atheroma regression is not observed in all patients. The purpose of the present study was to evaluate the determinants of atheroma progression despite achieving very low levels of LDL-C. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound in the TRUTH study. Of these, 33 patients who achieved an on-treatment LDL-C level of <70 mg/dl were divided into 2 groups according to increase in plaque volume (progressors, n= 16) or decrease in plaque volume (regressors, n= 17) during an 8-month follow-up period. At the 8-month follow-up, serum LDL-C and apolipoprotein B levels were significantly lower in progressors than in regressors; however, significant increases in high-density lipoprotein cholesterol and apolipoprotein AI and decreases in high-sensitivity C-reactive protein and oxidized LDL were observed only in regressors. The changes in the n-3 to n-6 polyunsaturated fatty acid ratios significantly differed between the 2 groups. Multivariate regression analysis showed that a decrease in the eicosapentaenoic acid + docosahexaenoic acid/arachidonic acid ratio was a significant predictor associated with atheroma progression (β= -0.512, p= 0.004). In conclusions, n-3 to n-6 polyunsaturated fatty acid ratios affected coronary artery plaque progression and regression in patients who achieved very low levels of LDL-C during statin therapy. PMID:24224137

  2. Small dense low density lipoprotein cholesterol and coronary heart disease: results from the Framingham Offspring Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We sought to establish reference values for a new direct assay for small dense LDL cholesterol (sdLDL-C) and to measure sdLDL-C concentrations in patients with established coronary heart disease (CHD) vs controls. Direct LDL-C and sdLDL-C were measured in samples from 3188 male and female participan...

  3. The effect of a high-intensity interval training program on high-density lipoprotein cholesterol in young men.

    PubMed

    Musa, Danladi I; Adeniran, Samuel A; Dikko, A U; Sayers, Stephen P

    2009-03-01

    This study examined the impact of an 8-week program of high-intensity interval training on high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and the atherogenic index (TC/HDL-C) in 36 untrained men ages 21-36 years. Participants were randomly assigned to an interval training group (n = 20) or a control group (n = 16). Participants in the experimental group performed 3.2 km of interval running (1:1 work:rest ratio) 3 times a week for 8 weeks at an intensity of 90% of maximal heart rate ( approximately 423 kcal per session). Results indicated significant pre- to posttraining changes in HDL-C (1.1 vs. 1.3 mmolxL, p < 0.0001) and TC/HDL-C (3.8 vs. 3.1, p < 0.0001) but no significant changes in TC (3.9 vs. 3.8 mmolxL, p > 0.05) with interval training. It was concluded that an 8-week program of high-intensity interval training is effective in eliciting favorable changes in HDL-C and TC/HDL-C but not TC in young adult men with normal TC levels. Our findings support the recommendations of high-intensity interval training as an alternative mode of exercise to improve blood lipid profiles for individuals with acceptable physical fitness levels. PMID:19209073

  4. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.

    PubMed

    Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P; Vadlamudi, Swarooparani; Gonzalez, Arlene J; Buchkovich, Martin L; Huyghe, Jeroen R; Fuchsberger, Christian; Jackson, Anne U; Wu, Ying; Civelek, Mete; Lusis, Aldons J; Gaulton, Kyle J; Sethupathy, Praveen; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L

    2015-12-01

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID:26637976

  5. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol

    PubMed Central

    Roman, Tamara S.; Marvelle, Amanda F.; Fogarty, Marie P.; Vadlamudi, Swarooparani; Gonzalez, Arlene J.; Buchkovich, Martin L.; Huyghe, Jeroen R.; Fuchsberger, Christian; Jackson, Anne U.; Wu, Ying; Civelek, Mete; Lusis, Aldons J.; Gaulton, Kyle J.; Sethupathy, Praveen; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S.; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L.

    2015-01-01

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r2 > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10−12). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT– haplotype] versus 16-fold [CC+ haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID:26637976

  6. Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice

    PubMed Central

    Wei, H; Averill, M M; McMillen, T S; Dastvan, F; Mitra, P; Subramanian, S; Tang, C; Chait, A; LeBoeuf, R C

    2014-01-01

    Background: Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition. Methods: To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I−/−) and apoA-I transgenic (apoA-Itg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies. Results: ApoA-I−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I−/− mice, apoA-Itg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-Itg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content. Conclusions: Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity. PMID:24567123

  7. Serum uric acid and low-density lipoprotein cholesterol levels are independent predictors of coronary artery disease in Asian Indian patients with type 2 diabetes mellitus

    PubMed Central

    Jayashankar, C. A.; Andrews, Henley Punnen; Vijayasarathi; Pinnelli, Venkata BharatKumar; Shashidharan, Basappaji; Nithin Kumar, H. N.; Vemulapalli, Swaapnika

    2016-01-01

    Aim: We aimed to identify the predictors of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (type 2 DM). Methods: About fifty Asian Indian patients with type 2 DM patients aged >40 years and fifty sex- and age-matched nondiabetic controls were enrolled for this study. Following complete medical history and baseline clinical data, laboratory investigations were performed to assess fasting and postprandial plasma glucose levels, lipid profile, blood urea, serum creatinine, and serum uric acid levels. Results: Body mass index (BMI), waist-to-hip ratio, serum uric acid, serum total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very LDL cholesterol were significantly higher among diabetic patients compared to controls. On univariate analysis, serum LDL cholesterol (odds ratio [OR]: 29.67, P < 0.001), serum uric acid (OR: 25.65, P < 0.001), low high-density lipoprotein (HDL) cholesterol (OR: 21.12, P < 0.001), hypertension (OR: 17.06, P < 0.001), family history of cardiovascular disease (CVD) (OR: 9.43, P = 0.002), and duration of diabetes (OR: 4.65, P = 0.03) were identified as predictors of CVD among diabetic patients. On multivariate regression, only LDL cholesterol (OR: 1.51, P = 0.002) and serum uric acid (OR: 1.21, P = 0.01) were the independent predictors of CAD among diabetic patients. Significant positive correlation of serum uric acid with duration of diabetes (r = 0.38, P = 0.006), BMI (r = 0.35, P = 0.01), triglycerides (r = 0.356, P = 0.01), LDL cholesterol (r = 0.38, P = 0.007), HDL cholesterol (r = −0.514, P < 0.001), and hypertension (r = 0.524, P < 0.001) was observed. Conclusion: Serum LDL cholesterol and hyperuricemia may serve as independent predictors of CAD among Asian Indian subjects with type 2 DM. PMID:27433067

  8. Relationship of High‐Density Lipoprotein Cholesterol With Periprocedural Myocardial Injury Following Elective Percutaneous Coronary Intervention in Patients With Low‐Density Lipoprotein Cholesterol Below 70 mg/dL

    PubMed Central

    Li, Xiao‐Lin; Guo, Yuan‐Lin; Zhu, Cheng‐Gang; Xu, Rui‐Xia; Qing, Ping; Wu, Na‐Qiong; Jiang, Li‐Xin; Xu, Bo; Gao, Run‐Lin; Li, Jian‐Jun

    2015-01-01

    Background Recent data showed inconsistent association of high‐density lipoprotein cholesterol (HDL‐C) with cardiovascular risk in patients with different levels of low‐density lipoprotein cholesterol (LDL‐C) or intensive statin therapy. This study sought to determine the relationship of HDL‐C with periprocedural myocardial injury following elective percutaneous coronary intervention (PCI) across a range of LDL‐C levels, especially in patients with LDL‐C <70 mg/dL. Methods and Results We enrolled 2529 consecutive patients with normal preprocedural cardiac troponin I (cTnI) who underwent elective PCI. The association between preprocedural HDL‐C and periprocedural myocardial injury was evaluated across LDL‐C levels, especially in patients with LDL‐C <70 mg/dL. The HDL‐C level was not predictive of periprocedural myocardial injury across the entire study cohort. However, among patients with LDL‐C <70 mg/dL, a 1 mg/dL increase in HDL‐C was associated with a 3% reduced risk for postprocedural cTnI above 1×upper limit of normal (ULN) (odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.004), a 3% reduced risk for postprocedural cTnI above 3×ULN odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.022), and a 3% reduced risk for postprocedural cTnI above 5×ULN (odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.017). The relation between plasma HDL‐C level and risk of postprocedural cTnI elevation above 1×ULN, 3×ULN, and 5×ULN was modified by LDL‐C level (all P for interaction <0.05). Conclusions Higher HDL‐C levels were associated with reduced risk of periprocedural myocardial injury only in patients with LDL‐C <70 mg/dL. PMID:25572484

  9. Cholesterol and Your Child

    MedlinePlus

    ... traveling together are called lipoproteins . Two kinds — low-density lipoprotein (LDL) and high-density lipoprotein (HDL) — are the ones that most of us have heard about. Low-density lipoproteins , or "bad cholesterol," are the primary cholesterol ...

  10. Antioxidative Activity after Rosuvastatin Treatment in Patients with Stable Ischemic Heart Disease and Decreased High Density Lipoprotein Cholesterol

    PubMed Central

    Park, Do-Sim; Park, Hyun Young; Rhee, Sang Jae; Kim, Nam-Ho; Oh, Seok Kyu; Jeong, Jin-Won

    2016-01-01

    Background and Objectives The clinical significance of statin-induced high-density lipoprotein cholesterol (HDL-C) changes is not well known. We investigated whether rosuvastatin-induced HDL-C changes can influence the anti-oxidative action of high-density lipoprotein particle. Subjects and Methods A total of 240 patients with stable ischemic heart disease were studied. Anti-oxidative property was assessed by paraoxonase 1 (PON1) activity. We compared the lipid profile and PON1 activity at baseline and at 8 weeks after rosuvastatin 10 mg treatment. Results Rosuvastatin treatment increased the mean HDL-C concentration by 1.9±9.2 mg/dL (6.4±21.4%). HDL-C increased in 138 patients (57.5%), but decreased in 102 patients (42.5%) after statin treatment. PON1 activity increased to 19.1% in all patients. In both, the patients with increased HDL-C and with decreased HDL-C, PON1 activity significantly increased after rosuvastatin treatment (+19.3% in increased HDL-C responder; p=0.018, +18.8% in decreased HDL-C responder; p=0.045 by paired t-test). Baseline PON1 activity modestly correlated with HDL-C levels (r=0.248, p=0.009); however, the PON1 activity evaluated during the course of the treatment did not correlate with HDL-C levels (r=0.153, p=0.075). Conclusion Rosuvastatin treatment improved the anti-oxidative properties as assessed by PON1 activity, regardless of on-treatment HDL-C levels, in patients with stable ischemic heart disease. PMID:27275167

  11. Gestational diabetes mellitus modulates neonatal high-density lipoprotein composition and its functional heterogeneity.

    PubMed

    Sreckovic, Ivana; Birner-Gruenberger, Ruth; Besenboeck, Carolin; Miljkovic, Milica; Stojakovic, Tatjana; Scharnagl, Hubert; Marsche, Gunther; Lang, Uwe; Kotur-Stevuljevic, Jelena; Jelic-Ivanovic, Zorana; Desoye, Gernot; Wadsack, Christian

    2014-11-01

    Gestational diabetes mellitus (GDM) is related to neonatal macrosomia and an increased risk of vascular events. We hypothesized that GDM exerts qualitative effects on neonatal high-density lipoprotein (HDL). HDL was isolated from control (n=11) and GDM maternal/neonatal donors (n=9) and subjected to shotgun proteomics. Differences in HDL mobility were assessed by FPLC and native gel-electrophoresis. Paraoxonase (PON1) activity, cholesterol ester-transfer protein (CETP) mass and activity, phospholipid, triglyceride and cholesterol concentrations were quantified with commercial kits. Total anti-oxidative capacity and cholesterol efflux capability of HDLs were measured. Four proteins involved in lipid metabolism, inflammation and innate immunity were differentially expressed between controls and GDM neonates. ApoM (decreased, p<0.05) and SAA1 (increased, p<0.05) showed the same differences on both, maternal and neonatal GDM HDL. Lower PON1 protein expression was corroborated by lower activity (p<0.05) which in turn was associated with attenuated anti-oxidant capacity of GDM HDL. Protein changes were accompanied by increased levels of triglycerides and decreased levels of cholesterol esters, respectively. The observed differences in GDM HDL lipid moiety may be related to CETP mass and activity alterations. The rate of cholesterol efflux from term trophoblasts to maternal and from placental endothelial cells to neonatal GDM HDL was impaired (p<0.05). In conclusion, GDM causes changes in HDL composition and is intimately associated with impaired cholesterol efflux capability as well as diminished anti-oxidative particle properties. Remodeling of neonatal GDM HDL in utero supports the hypothesis that maternal conditions in pregnancy impact neonatal lipoprotein metabolism. PMID:25130684

  12. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.

    PubMed

    Badimon, J J; Badimon, L; Fuster, V

    1990-04-01

    The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration. PMID:2318976

  13. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.

    PubMed Central

    Badimon, J J; Badimon, L; Fuster, V

    1990-01-01

    The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration. Images PMID:2318976

  14. Achieving cholesterol targets by individualizing starting doses of statin according to baseline low-density lipoprotein cholesterol and coronary artery disease risk category: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) study

    PubMed Central

    Ur, Ehud; Langer, Anatoly; Rabkin, Simon W; Calciu, Cristina-Dana; Leiter, Lawrence A

    2010-01-01

    BACKGROUND: Despite an increasing body of evidence on the benefit of lowering elevated levels of low-density lipoprotein cholesterol (LDL-C), there is still considerable concern that patients are not achieving target LDL-C levels. OBJECTIVE: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) trial tested whether an algorithm-based statin dosing approach would enable patients to achieve LDL-C and total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio targets quickly. METHODS: Subjects requiring statin therapy, but with an LDL-C level of 5.7 mmol/L or lower, and triglycerides of 6.8 mmol/L or lower at screening participated in the 12-week study, which had two open-label, six-week phases: a treatment period during which patients received 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin based on an algorithm incorporating baseline LDL-C value and cardiovascular risk; and patients who achieved both LDL-C and TC/HDL-C ratio targets at six weeks continued on the same atorvastatin dose. Patients who did not achieve both targets received dose uptitration using a single-step titration regimen. The primary efficacy outcome was the proportion of patients achieving target LDL-C levels after 12 weeks. RESULTS: Of 2016 subjects screened at 88 Canadian sites, 1258 were assigned to a study drug (1101 were statin-free and 157 were statin-treated at baseline). The proportion of subjects who achieved LDL-C targets after 12 weeks of treatment was 86% (95% CI 84% to 88%) for statin-free patients and 54% (95% CI 46% to 61%) for statin-treated patients. Overall, 1003 subjects (80%; 95% CI 78% to 82%) achieved both lipid targets. CONCLUSIONS: Algorithm-based statin dosing enables patients to achieve LDL-C and TC/HDL-C ratio targets quickly, with either no titration or a single titration. PMID:20151053

  15. Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men.

    PubMed

    Talmud, P J; Hawe, E; Robertson, K; Miller, G J; Miller, N E; Humphries, S E

    2002-03-01

    The effects of common variants of cholesteryl ester transfer protein (CETP) (TaqIB), hepatic lipase (HL) (-514C>T), lipoprotein lipase (LPL) (S447X) and lecithin cholesterol acyl transferase (LCAT) (S208T) on the determination of high density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels were examined in 2773 healthy middle-aged men participating in the second Northwick Park Heart Study. The extent of gene:gene, gene:smoking and gene:alcohol interactions were determined. For HDL-C levels, only CETP genotype was associated with significant effects (p&0.0001), with the B2 allele being associated with higher levels in both smokers and non-smokers. This interaction was significant at the lowest tertile of TG, suggesting that TG levels were rate limiting. As previously reported, CETP, LPL and HL genotypes were all associated with significant effects on apoAI levels (all p&0.01), with carriers of the rare alleles having higher levels and with no evidence of heterogeneity of effects in smokers and non-smokers. LCAT genotype was not associated with significant effects on either trait. There was no significant interaction between any of the genotypes and alcohol consumption on either HDL-C or apoAI levels. All genotypic effects were additive for HDL-C and apoAI. Environmental and TG levels explained more than 20% and 5.5% of the variance in HDL-C and apoAI, respectively. The novel aspect of this finding is that genetic variation at these loci explained in total only 2.5% of the variance in HDL-C and 1.89% of the variance in apoAI levels. Thus despite the key roles played by these enzymes in HDL metabolism, variation at these loci, at least as detected by these common genotypes, contributes minimally to the variance in HDL-C and apoAI levels in healthy men, highlighting the polygenic and multifactorial control of HDL-C. PMID:12174215

  16. Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component.

    PubMed

    Herzog, Eva; Pragst, Ingo; Waelchli, Marcel; Gille, Andreas; Schenk, Sabrina; Mueller-Cohrs, Jochen; Diditchenko, Svetlana; Zanoni, Paolo; Cuchel, Marina; Seubert, Andreas; Rader, Daniel J; Wright, Samuel D

    2016-08-01

    Human apolipoprotein A-I preparations reconstituted with phospholipids (reconstituted high-density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A-I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release. Observations from several animal models and in vitro studies suggest that the extent of hepatic transaminase release (alanine aminotransferase [ALT]) correlates with the movement of hepatic cholesterol into the blood after infusion. Both the amount of ALT release and cholesterol movement were dependent on the amount and type of phospholipid present in the reconstituted HDL. As cholesterol is known to dissolve readily in phospholipid, an HDL preparation was loaded with cholesterol before infusion into rats to assess the role of diffusion of cholesterol out of the liver and into the reconstituted HDL. Cholesterol-loaded HDL failed to withdraw cholesterol from tissues and subsequently failed to cause ALT release. To investigate further the role of cholesterol diffusion, we employed mice deficient in SR-BI, a transporter that facilitates spontaneous movement of cholesterol between cell membranes and HDL. These mice showed substantially lower movement of cholesterol into the blood and markedly lower ALT release. We conclude that initial depletion of hepatic cholesterol initiates transient ALT release in response to infusion of reconstituted HDL. This effect may be controlled by appropriate choice of the type and amount of phospholipid in reconstituted HDL. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26651060

  17. Technical note: The role of circulating low-density lipoprotein levels as a phenotypic marker for Holstein cholesterol deficiency in dairy cattle.

    PubMed

    Saleem, S; Heuer, C; Sun, C; Kendall, D; Moreno, J; Vishwanath, R

    2016-07-01

    With the recent discovery of a Holstein cholesterol deficiency (HCD) haplotype, the USDA has labeled many dairy animals as HCD carriers based on haplotype and pedigree analysis. We set out to investigate the effect of HCD status on various cholesterol transport molecules, namely low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides in both males and females. A genome-wide association study was also conducted to narrow down the genomic region correlated with varying LDL-C levels. In the study, 34 HCD carrier animals showed significantly lower cholesterol and LDL-C levels compared with their 34 closely related, non-HCD controls. The genome-wide association study based on 73 animals using 56,198 SNP markers revealed an association with chromosome 11 in the region of 66,218,925 to 66,946,746 bp. We also tested the effect of HCD status on sperm quality traits using fresh ejaculates and frozen-thawed semen samples, but did not find any discriminating effects. Our study has demonstrated the use of LDL-C as a key phenotypic marker for determining HCD status in dairy cattle and this is the first study that clearly shows a cause-effect relationship of the HCD haplotype on circulating LDL-C. PMID:27108167

  18. Reflex Testing for Carbohydrate-Deficient Transferrin (CDT) in Insurance Applicants with Elevated High Density Lipoprotein Cholesterol (HDL).

    PubMed

    Singh, Gurmukh

    2015-01-01

    Objectives .- Ascertain the utility of testing carbohydrate deficient transferrin (CDT) levels in insurance applicants with elevated high density lipoprotein cholesterol (HDL) levels. Background .- Chronic alcoholism is not uncommon and is a risk factor for health and longevity and thus of interest to providers of insurance. A number of tests serve as markers of alcohol use, eg, blood alcohol level, elevated liver enzymes, ethyl glucuronide in urine, whole blood associated aldehyde (WBAA), macrocytosis, elevated HDL, elevated CDT and others. WBAA and CDT are usually only done, if some other screening test suggests alcohol use. HDL testing is routinely done for assessing cardiac risk, however, chronic alcohol intake tends to raise HDL and some insurance providers reflex to CDT testing when HDL is elevated. Methods .- A number of the clients of Heritage Labs Inc. have rules in place to test for CDT levels in specimens showing elevated HDL levels. The commonest HDL level that serves as the trigger for reflex testing for CDT is 80mg/dL. The results of this practice were analyzed to assess the utility of reflex testing for CDT to identify chronic alcohol abusers among the applicants. Results .- In examining the results of CDT levels done as a reflex test due to elevated HDL levels, about 2% of the applicants, 0.7% of women and 3% of men, tested positive for elevated CDT levels. Conclusions .- The incidence of elevated CDT levels is high enough to warrant routinely testing for this analyte in applicants, especially men, with high HDL levels. PMID:27584808

  19. The importance of low serum levels of high-density lipoprotein cholesterol (HDL-C) as a cardiovascular risk factor.

    PubMed

    Espinosa-Larrañaga, Francisco; Vejar-Jalaf, Margarita; Medina-Santillán, Roberto

    2005-10-01

    In order to discuss and establish a joint position on the treatment of low serum levels of high-density lipoprotein cholesterol (HDL-C), a group of experts involved in the care of people with dyslipidaemia and at risk of cardiovascular disease met in Miami, Florida, U.S., on 5th and 6th March 2005. The experts came from the Latin American countries Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico and Venezuela and had at least five years of experience in the care of patients with dyslipidaemia and low HDL-C. The main objective of the meeting was to discuss and propose a treatment for low serum HDL-C levels as a cardiovascular risk factor in patients and to create a group of useful recommendations in this regard, applicable to the daily clinical practice of physicians dealing with patients with dyslipidaemia and cardiovascular disease. This document describes the methodology developed to obtain these recommendations and presents the results of this academic meeting. PMID:16342610

  20. Systematic review of green tea epigallocatechin gallate in reducing low-density lipoprotein cholesterol levels of humans.

    PubMed

    Momose, Yuko; Maeda-Yamamoto, Mari; Nabetani, Hiroshi

    2016-09-01

    We conducted a systematic review of the literature for the ability of green tea epigallocatechin gallate (EGCG) to lower low-density lipoprotein cholesterol (LDL-C). Study subjects were limited to healthy individuals and randomized, controlled trials on human serum lipid levels, especially LDL-C, conducted. A total of 17 trials (n = 1356) met all of the inclusion criteria. According to weighted mean differences for changes from baseline with 95% confidence intervals (CI), 107-856 mg/d of EGCG for 4 to 14 weeks reduced LDL-C by -9.29 mg/dl (95% CI, -12.27 to -6.31). Sub-analysis was performed to compare the EGCG lowering effect on LDL-C between non-obese and obese subjects, EGCG dose, baseline of LDL-C levels, or BMI. We concluded that consumption of green tea EGCG resulted in a significant reduction of LDL-C at any baseline level and any dose between 107 and 856 mg/d, and the effect size was slightly dependent on the baseline lipid level of the subjects. PMID:27324590

  1. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol.

    PubMed

    Belalcazar, L M; Ballantyne, C M

    1998-01-01

    Because patients with low high-density lipoprotein (HDL) cholesterol (HDL-C) are at high risk for clinical coronary artery disease (CAD) events, these patients require aggressive treatment with lifestyle modifications-increased exercise, smoking cessation, and weight loss in overweight patients-and available pharmacological agents. Drugs that raise HDL-C include nicotinic acid, fibric acid derivatives, estrogens, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), alpha-blockers, and alcohol. However, all agents that increase HDL-C may not have the same clinical benefit, just as, as shown in genetic studies in humans and mice, genetic causes of high HDL-C do not always protect against CAD, nor do genetic causes of low HDL-C always increase risk for CAD. Better understanding of the complexities of HDL metabolism and the mechanisms by which HDL protects against CAD is needed to enable the development of new therapeutic strategies--novel drugs or gene delivery systems--to increase HDL-C and reduce CAD events. The statins are the agents with the greatest evidence for slowing progression of CAD and reducing clinical events in patients with low HDL-C, but additional research is needed to determine the potential benefits of additional interventions that increase HDL-C, including combination therapy, which may provide greater improvements in the entire lipid profile. PMID:9790415

  2. Adverse effect of pregnancy on high density lipoprotein (HDL) cholesterol in young adult women. The CARDIA Study. Coronary Artery Risk Development in Young Adults.

    PubMed

    Lewis, C E; Funkhouser, E; Raczynski, J M; Sidney, S; Bild, D E; Howard, B V

    1996-08-01

    The authors analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study in order to examine associations between parity and lipoproteins. Of 2,787 women recruited in 1985-1986, 2,534 (91%) returned in 1987-1988 and 2,393 (86%) returned in 1990-1991 for repeat evaluations. Two-year change (1987-1988 to 1985-1986) in high density lipoprotein (HDL) cholesterol was significantly different among the parity groups. HDL cholesterol decreased in women who had their first pregnancy of at least 28 weeks duration during follow-up (mean +/- standard error, -3.5 +/- 1.2 mg/dl), and this change was significantly different from the increase in women parous at baseline who had no further pregnancies (2.5 +/- 0.3 mg/dl) and in nullipara (2.4 +/- 0.3 mg/dl). There was a nonsignificant trend for a greater decrease in HDL2 cholesterol fraction in the primipara compared with the other groups. The HDL cholesterol decrease remained significant after controlling for race, age, education, oral contraceptive use, and changes in body mass index, waist-hip ratio, physical activity, smoking status, and alcohol intake. Change in HDL cholesterol was also significantly different among the parity groups in analyses of pregnancies that occurred during the subsequent 3 years of follow-up. There were no differences for change in LDL cholesterol or triglycerides. Potential mechanisms for a detrimental effect of pregnancy on HDL cholesterol include hormonal, body composition, or life-style/behavioral changes. PMID:8686693

  3. Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

    PubMed Central

    Vrins, Carlos L. J.; Out, Ruud; van Santbrink, Peter; van der Zee, André; Mahmoudi, Tokameh; Groenendijk, Martine; Havekes, Louis M.; van Berkel, Theo J. C.; van Dijk, Ko Willems; Biessen, Erik A. L.

    2013-01-01

    Background The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr−/− mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl−/− mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels. PMID:23469003

  4. Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol.

    PubMed Central

    Romanenko, Victor G; Rothblat, George H; Levitan, Irena

    2002-01-01

    Membrane potential of aortic endothelial cells under resting conditions is dominated by inward-rectifier K(+) channels belonging to the Kir 2 family. Regulation of endothelial Kir by membrane cholesterol was studied in bovine aortic endothelial cells by altering the sterol composition of the cell membrane. Our results show that enriching the cells with cholesterol decreases the Kir current density, whereas depleting the cells of cholesterol increases the density of the current. The dependence of the Kir current density on the level of cellular cholesterol fits a sigmoid curve with the highest sensitivity of the Kir current at normal physiological levels of cholesterol. To investigate the mechanism of Kir regulation by cholesterol, endogenous cholesterol was substituted by its optical isomer, epicholesterol. Substitution of approximately 50% of cholesterol by epicholesterol results in an early and significant increase in the Kir current density. Furthermore, substitution of cholesterol by epicholesterol has a stronger facilitative effect on the current than cholesterol depletion. Neither single channel properties nor membrane capacitance were significantly affected by the changes in the membrane sterol composition. These results suggest that 1) cholesterol modulates cellular K(+) conductance by changing the number of the active channels and 2) that specific cholesterol-protein interactions are critical for the regulation of endothelial Kir. PMID:12496090

  5. Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols.

    PubMed

    Hazen, S L; Hsu, F F; Duffin, K; Heinecke, J W

    1996-09-20

    Oxidation of low density lipoprotein (LDL) may be of critical importance in triggering the pathological events of atherosclerosis. Myeloperoxidase, a heme protein secreted by phagocytes, is a potent catalyst for LDL oxidation in vitro, and active enzyme is present in human atherosclerotic lesions. We have explored the possibility that reactive intermediates generated by myeloperoxidase target LDL cholesterol for oxidation. LDL exposed to the myeloperoxidase-H2O2-Cl- system at acidic pH yielded a family of chlorinated sterols. The products were identified by mass spectrometry as a novel dichlorinated sterol, cholesterol alpha-chlorohydrin (6beta-chlorocholestane-(3beta,5alpha)-diol), cholesterol beta-chlorohydrin (5alpha-chlorocholestane-(3beta, 6beta)-diol), and a structurally related cholesterol chlorohydrin. Oxidation of LDL cholesterol by myeloperoxidase required H2O2 and Cl-, suggesting that hypochlorous acid (HOCl) was an intermediate in the reaction. However, HOCl failed to generate chlorinated sterols under chloride-free conditions. Since HOCl is in equilibrium with molecular chlorine (Cl2) through a reaction which requires Cl- and H+, this raised the possibility that Cl2 was the actual chlorinating intermediate. Consonant with this hypothesis, HOCl oxidized LDL cholesterol in the presence of Cl- and at acidic pH. Moreover, in the absence of Cl- and at neutral pH, Cl2 generated the same family of chlorinated sterols as the myeloperoxidase-H2O2-Cl- system. Finally, direct addition of Cl2 to the double bond of cholesterol accounts for dichlorinated sterol formation by myeloperoxidase. Collectively, these results indicate that Cl2 derived from HOCl is the chlorinating intermediate in the oxidation of cholesterol by myeloperoxidase. Our observations suggest that Cl2 generation in acidic compartments may constitute one pathway for oxidation of LDL cholesterol in the artery wall. PMID:8798498

  6. Impaired Cholesterol Efflux Capacity of High-Density Lipoprotein Isolated From Interstitial Fluid in Type 2 Diabetes Mellitus—Brief Report

    PubMed Central

    Tietge, Uwe J.F.; Dikkers, Arne; Parini, Paolo; Angelin, Bo; Rudling, Mats

    2016-01-01

    Objective— Patients with type 2 diabetes mellitus (T2D) have an increased risk of cardiovascular disease, the mechanism of which is incompletely understood. Their high-density lipoprotein (HDL) particles in plasma have been reported to have impaired cholesterol efflux capacity. However, the efflux capacity of HDL from interstitial fluid (IF), the starting point for reverse cholesterol transport, has not been studied. We here investigated the cholesterol efflux capacity of HDL from IF and plasma from T2D patients and healthy controls. Approach and Results— HDL was isolated from IF and peripheral plasma from 35 T2D patients and 35 age- and sex-matched healthy controls. Cholesterol efflux to HDL was determined in vitro, normalized for HDL cholesterol, using cholesterol-loaded macrophages. Efflux capacity of plasma HDL was 10% lower in T2D patients than in healthy controls, in line with previous observations. This difference was much more pronounced for HDL from IF, where efflux capacity was reduced by 28% in T2D. Somewhat surprisingly, the efflux capacity of HDL from IF was lower than that of plasma HDL, by 15% and 32% in controls and T2D patients, respectively. Conclusion— These data demonstrate that (1) HDL from IF has a lower cholesterol efflux capacity than plasma HDL and (2) the efflux capacity of HDL from IF is severely impaired in T2D when compared with controls. Because IF comprises the compartment where reverse cholesterol transport is initiated, the marked reduction in cholesterol efflux capacity of IF-HDL from T2D patients may play an important role for their increased risk to develop atherosclerosis. PMID:27034474

  7. Cholesterol absorption.

    PubMed

    Ostlund, Richard E

    2002-03-01

    Cholesterol absorption is a key regulatory point in human lipid metabolism because it determines the amount of endogenous biliary as well as dietary cholesterol that is retained, thereby influencing whole body cholesterol balance. Plant sterols (phytosterols) and the drug ezetimibe reduce cholesterol absorption and low-density lipoprotein cholesterol in clinical trials, complementing the statin drugs, which inhibit cholesterol biosynthesis. The mechanism of cholesterol absorption is not completely known but involves the genes ABC1, ABCG5, and ABCG8, which are members of the ATP-binding cassette protein family and appear to remove unwanted cholesterol and phytosterols from the enterocyte. ABC1 is upregulated by the liver X (LXR) and retinoid X (RXR) nuclear receptors. Acylcholesterol acytransferase-2 is an intestinal enzyme that esterifies absorbed cholesterol and increases cholesterol absorption when dietary intake is high. New clinical treatments based on better understanding of absorption physiology are likely to substantially improve clinical cholesterol management in the future. PMID:17033296

  8. Distinct Roles of Apolipoproteins A1 and E in the Modulation of High-Density Lipoprotein Composition and Function.

    PubMed

    Filou, Serafoula; Lhomme, Marie; Karavia, Eleni A; Kalogeropoulou, Christina; Theodoropoulos, Vassilis; Zvintzou, Evangelia; Sakellaropoulos, George C; Petropoulou, Peristera-Ioanna; Constantinou, Caterina; Kontush, Anatol; Kypreos, Kyriakos E

    2016-07-12

    In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apolipoprotein E (Apoe) is also capable of promoting the de novo biogenesis of HDL with the participation of ATP binding cassette A lipid transporter member 1 (Abca1) and plasma enzyme lecithin:cholesterol acyltransferase (Lcat), in a manner independent of a functional Apoa1. Here, we performed a comparative analysis of the functions of these HDL subpopulations. Specifically, Apoe and Apoa1 double-deficient (Apoe(-/-) × Apoa1(-/-)) mice were infected with APOA1- or APOE3-expressing adenoviruses, and APOA1-containing HDL (APOA1-HDL) and APOE3-containing HDL (APOE3-HDL), respectively, were isolated and analyzed by biochemical and physicochemical methods. Western blot and lipidomic analyses indicated significant differences in the apolipoprotein and lipid composition of the two HDL species. Moreover APOE3-HDL presented a markedly reduced antioxidant potential and Abcg1-mediated cholesterol efflux capacity. Surprisingly, APOE3-HDL but not APOA1-HDL attenuated LPS-induced production of TNFα in RAW264.7 cells, suggesting that the anti-inflammatory effects of APOA1 are dependent on APOE expression. Taken together, our data indicate that APOA1 and APOE3 recruit different apolipoproteins and lipids on the HDL particle, leading to structurally and functionally distinct HDL subpopulations. The distinct role of these two apolipoproteins in the modulation of HDL functionality may pave the way toward the development of novel pharmaceuticals that aim to improve HDL functionality. PMID:27332083

  9. Low-Density Lipoprotein Cholesterol Levels and Statin Treatment by HIV Status Among Multicenter AIDS Cohort Study Men

    PubMed Central

    Fu, Wei; Zikusoka, Michelle N.; Jacobson, Lisa P.; Witt, Mallory D.; Palella, Frank J.; Kingsley, Lawrence A.; Post, Wendy S.; Brown, Todd T.

    2015-01-01

    Abstract Treating cardiovascular disease (CVD) risk factors, including dyslipidemia, is important in HIV care. Low-density lipoprotein cholesterol (LDL-c) target achievement is a readily available benchmark for dyslipidemia control, although use of this target is not uniformly endorsed by professional societies. We examined whether HIV serostatus is associated with not achieving LDL-c target. Among Multicenter AIDS Cohort Study (MACS) participants completing visit 56 (10/1/2011–3/31/2012), we categorized each man as on or off statin therapy and used NCEP ATP III guidelines to determine if each man was at LDL-c target or not at target. We compared proportions of men not at target and determined predictors using multivariate logistic regression. Sixty of 543 (11.1%) HIV-infected men and 87 of 585 (14.9%) HIV-uninfected men not receiving statin therapy were not at target (p=0.07), while 31 of 230 (13.5%) HIV-infected and 29 of 204 (14.2%) HIV-uninfected men receiving statin therapy were not at target (p=0.82). Factors associated with not being at target (among men not receiving statin therapy) included current smoking (OR=2.31, 95% CI 1.31, 4.06) and a diagnosis of hypertension (OR=4.69, 95% CI 2.68, 8.21). Factors associated with not being at target (among men receiving statin therapy) included current smoking (OR=2.72, 95% CI 1.30, 5.67) and diabetes (OR=5.31, 95% CI 2.47, 11.42). HIV-infected and HIV-uninfected men receiving statin therapy demonstrated similar nonachievement of LDL-c targets. Comorbidities (e.g., diabetes) lowered targets and may explain why goals were less likely to be met. PMID:25664922

  10. Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

    PubMed Central

    Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

    2013-01-01

    Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

  11. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    PubMed Central

    An, Ping; Straka, Robert J.; Pollin, Toni I.; Feitosa, Mary F.; Wojczynski, Mary K.; Daw, E. Warwick; O'Connell, Jeffrey R.; Gibson, Quince; Ryan, Kathleen A.; Hopkins, Paul N.; Tsai, Michael Y.; Lai, Chao-Qiang; Province, Michael A.; Ordovas, Jose M.; Shuldiner, Alan R; Arnett, Donna K.; Borecki, Ingrid B.

    2014-01-01

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted. PMID:24604477

  12. Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

    PubMed Central

    Sidore, Carlo; Kang, Hyun M.; Jackson, Anne U.; Piras, Maria Grazia; Usala, Gianluca; Maninchedda, Giuseppe; Sassu, Alessandro; Serra, Fabrizio; Palmas, Maria Antonietta; Wood, William H.; Njølstad, Inger; Laakso, Markku; Hveem, Kristian; Tuomilehto, Jaakko; Lakka, Timo A.; Rauramaa, Rainer; Boehnke, Michael; Cucca, Francesco; Uda, Manuela; Schlessinger, David; Nagaraja, Ramaiah; Abecasis, Gonçalo R.

    2011-01-01

    Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. PMID:21829380

  13. Correlation between high density lipoprotein-cholesterol and remodeling index in patients with coronary artery disease: IDEAS (IVUS diagnostic evaluation of atherosclerosis in Singapore)-HDL study.

    PubMed

    Lee, Chi-Hang; Tai, Bee-Choo; Lim, Gek-Hsiang; Chan, Mark Y; Low, Adrian F; Tan, Kathryn C; Chia, Boon-Lock; Tan, Huay-Cheem

    2012-01-01

    Serum level of high density lipoprotein (HDL)-cholesterol is associated with risk of coronary artery disease. We correlated the serum level of cholesterol with coronary artery remodeling index of patients with coronary artery disease. A total of 120 patients with de novo lesions located in native coronary artery were studied. Remodeling index was based on intravascular ultrasound (IVUS) interrogation of the lesions using the static approach, and was defined as external elastic membrane (EEM) area at lesion/average EEM area at proximal and distal reference segments. The average remodeling index was 0.9 (SD: 0.2). The remodeling index was not associated with any of the demographic and coronary risk factors. Stable angina was associated with a low remodeling index. Remodeling index correlated with white blood cell count and HDL-cholesterol, but not with total cholesterol, LDL-cholesterol and triglyceride. In the multiple linear regression analysis, HDL-cholesterol and procedure indication were the only 2 significant predictors of remodeling index. An increase of 1 mg/dL of HDL-cholesterol resulted in a decrease of 0.003 (95% CI: 0.0001, 0.007; P = 0.046) in remodeling index, after adjusting for procedural indications. When stratified according to diabetic status, the negative correlation persisted in non-diabetic (P = 0.023), but not in diabetic, patients (P = 0.707). We found a negative correlation between HDL-cholesterol level and remodeling index. Diabetic status may have an influence on the observed relationship. PMID:21197580

  14. Cholesterol efflux to high-density lipoproteins and apolipoprotein A-I phosphatidylcholine complexes is inhibited by ethanol: role of apolipoprotein structure and cooperative interaction of phosphatidylcholine and cholesterol.

    PubMed

    Avdulov, N A; Chochina, S V; Igbavboa, U; Wood, W G

    2000-08-29

    There is a substantial body of evidence showing that moderate alcohol consumption is associated with a reduced risk of cardiovascular morbidity and mortality. One of the factors thought to contribute to this reduction in risk is an increase in the level of high-density lipoproteins (HDL) correlated with alcohol consumption. However, HDL levels are elevated in heavy drinkers, but their risk of vascular disease is greater compared with that of moderate drinkers. Ethanol at concentrations observed in heavy drinkers and alcoholics may directly act on HDL and apolipoproteins and in turn modify cholesterol efflux. In this paper, we show that ethanol significantly inhibited cholesterol efflux from fibroblasts to HDL and to apolipoprotein A-I (apoA-I) complexed with phosphatidylcholine (PC). Ethanol significantly inhibited binding of PC to apoA-I, inhibited incorporation of cholesterol only when apoA-I contained PC, and did not alter incorporation of cholesterol into HDL. ApoA-I structure was altered by ethanol as monitored by steady-state fluorescence polarization of tryptophan residues. The absence of ethanol effects on incorporation of cholesterol into HDL versus inhibition of cholesterol incorporation into the apoA-I-PC complex suggests that the effects of ethanol on cholesterol efflux mediated by HDL involve interaction with the cell surface and that efflux mediated by the apoA-I-PC complex is a combination of aqueous diffusion and contact with the cell surface. In addition, effects of ethanol on apoA-I suggest that pre-beta-HDL or lipid-free apoA-I may be more perturbed by ethanol than mature HDL, and such effects may be pathophysiological with respect to the process of reverse cholesterol transport in heavy drinkers and alcoholics. PMID:10956052

  15. Increased serum triglyceride clearance and elevated high-density lipoprotein 2 and 3 cholesterol during treatment of primary hypertriglyceridemia with bezafibrate☆

    PubMed Central

    Sakuma, Nagahiko; Ikeuchi, Reiko; Hibino, Takeshi; Yoshida, Takayuki; Mukai, Seiji; Akita, Sachie; Yajima, Kazuhiro; Miyabe, Hiromichi; Goto, Toshihiko; Takada, Norio; Ohte, Nobuyuki; Kunimatu, Mitoshi; Kimura, Genjiro

    2003-01-01

    Background Hypertriglyceridemia accompanied by low levels of high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. High-density lipoprotein 2 (HDL2) and 3 (HDL3) are believed to suppress the progress of atherosclerosis through reverse cholesterol transport. As a result, peripheral tissues can be protected against excessive accumulation of cholesterol. Although bezafibrate is known to accelerate the increase of HDL-C, results are not standardized regarding increases of HDL3 and HDL2 subfractions. Objective This study assessed the effects of bezafibrate on serum triglyceride (TG) fractional clearance rate (K2) and HDL2 and HDL3 cholesterol (HDL2-C and HDL3-C, respectively) levels in patients with primary hypertriglyceridemia (serum TG ≥150 mg/dL). Methods Outpatients with primary hypertriglyceridemia were enrolled in this 8-week study conducted at the Third Department of Internal Medicine, Nagoya City University Hospital (Nagoya, Japan). Oral bezafibrate was administered at a dose of 400 mg/d (200-mg tablet BID, morning and evening) for 8 weeks. After 8 weeks, serum levels of total cholesterol (TC), TG, HDL-C, HDL2-C, and HDL3-C were measured. A fat emulsion tolerance test to assess K2 and measurements of plasma lipoprotein lipase (LPL) mass, LPL activity, and hepatic triglyceride lipase (HTGL) activity in postheparin plasma were performed before bezafibrate administration and after the course of treatment. Results Sixteen patients (10 men, 6 women; mean [SD] age, 54 [12] years [range, 30–69 years]; mean [SD] body mass index, 23 [2] kg/m2) entered the study. The following findings were observed in male and female patients after 8 weeks of treatment. A statistically significant reduction was observed in mean serum TG level (P<0.01). Significant increases were seen in HDL-C, HDL2-C, and HDL3-C (all P<0.01), K2 (P<0.01), and in plasma LPL mass (P<0.01) and LPL activity (P<0.05). TC level and HTGL activity did not change

  16. Home-Use Tests - Cholesterol

    MedlinePlus

    ... this test does: This is a home-use test kit to measure total cholesterol. What cholesterol is: Cholesterol is a fat (lipid) in your blood. High-density lipoprotein (HDL) ("good" cholesterol) helps protect your heart, but low-density lipoprotein (LDL) ("bad" cholesterol) can clog the arteries of your ...

  17. [Effect of raw and cooked nopal (Opuntia ficus indica) ingestion on growth and profile of total cholesterol, lipoproteins, and blood glucose in rats].

    PubMed

    Cárdenas Medellín, M L; Serna Saldívar, S O; Velazco de la Garza, J

    1998-12-01

    Two different concentrations (approx. 6 and 12%) and two presentations (raw and cooked) of dehydrated nopal were fed to laboratory rats and growth and serum total cholesterol, lipoprotein profile and glucose determined. Samples of raw and cooked nopal were chemically characterized for moisture, protein, ash, crude fiber, ether extract, total dietary fiber, reducing sugars, amino acids, minerals and gross energy. Cooking slightly affected some of the nutrients analyzed. After one month feeding, blood was withdrawn via intracardiac puncture and serum glucose, total cholesterol, HDL, LDL, and VLDL were determined. Rats fed 12% nopal had lower weight gains (P < 0.05) when compared with counterparts fed 6% nopal or the control diet. Consumption of nopal did not affect (P > 0.05) glucose, total cholesterol and HDL cholesterol levels. However, rats fed raw nopal at the 12% concentration level had a 34% reduction in LDL cholesterol levels; thus, it was concluded that raw nopal had a potentially beneficial effect for hypercholesterolemic individuals. PMID:10347696

  18. Comparative Study of Tomato and Tomato Paste Supplementation on the Level of Serum Lipids and Lipoproteins Levels in Rats Fed With High Cholesterol

    PubMed Central

    Khayat Nouri, Mir Hadi; Namvaran Abbas Abad, Ali

    2013-01-01

    Background Hypercholesterolemia is one of the risk factors of cardiovascular diseases. Increased blood cholesterol affects general health and increases mortality due to cardiovascular disease. Poor nutrition increases LDL cholesterol and decreases LDL receptor activities in the liver. Scientists have shown that consumption of antioxidants can reduce hypercholesterolemia and proved benefits of fruit and vegetables. Tomato reduces oxidative stress by increasing serum total antioxidant level. Objectives This study compared the tomato and tomato paste supplementation on the level of serum lipids and lipoproteins in rats fed with high cholesterol. Materials and Methods In this study, four male rat groups (10 rats per group) were used. Control group received basal diet, second group received basal diet and 2% cholesterol (Chol), third and fourth groups received basal diet, 2% cholesterol tomato and tomato paste respectively (20 percent of the diet) for a month. Then serum TC, LDL, HDL and TG were measured. Results Results showed that in Chol group, all lipids increased significantly (P < 0.05) except HDL compared to the control group. Tomato and tomato paste supplementation decreased TC, LDL and TG concentration significantly (P < 0.05) compared to Chol group. Tomato paste had the higher effect on lipids decreasing than tomato. Conclusions Decreases of TC, LDL and TG may be related to tomato antioxidant effect. This course in human required more investigations. PMID:24082999

  19. Phenolic-extract from argan oil (Argania spinosa L.) inhibits human low-density lipoprotein (LDL) oxidation and enhances cholesterol efflux from human THP-1 macrophages.

    PubMed

    Berrougui, Hicham; Cloutier, Martin; Isabelle, Maxim; Khalil, Abdelouahed

    2006-02-01

    Argan oil is rich in unsaturated fatty acids, tocopherol and phenolic compounds. These protective molecules make further study of its cardiovascular diseases (CVDs) action interesting. Furthermore, no previous study has explored the antioxidant activity of argan oil in comparison with olive oil. The present study was conducted to evaluate the beneficial properties of Virgin argan oil phenolic extracts (VAO-PE) towards CVD by: (A) protecting human (low-density lipoprotein, LDL) against lipid peroxidation and (B) promoting high-density lipoprotein (HDL)-mediated cholesterol efflux. Human LDLs were oxidized by incubation with CuSO(4) in the presence of different concentrations of VAO-PE (0-320mug/ml). LDL lipid peroxidation was evaluated by conjugated diene and MDA formation as well as Vitamin E disappearance. Incubation of LDL with VAO-PE significantly prolonged the lag-phase and lowered the progression rate of lipid peroxidation (P<0.01) and reduced the disappearance of Vitamin E in a concentration-dependent manner. Incubation of HDL with VAO-PE significantly increased the fluidity of the HDL phospholipidic bilayer (P=0.0004) and HDL-mediated cholesterol efflux from THP-1 macrophages. These results suggest that Virgin argan oil provides a source of dietary phenolic antioxidants, which prevent cardiovascular diseases by inhibiting LDL-oxidation and enhancing reverse cholesterol transport. These properties increase the anti-atherogenic potential of HDL. PMID:16019008

  20. Dietary cholesterol modulates the excitability of rabbit hippocampal CA1 pyramidal neurons

    PubMed Central

    Wang, Desheng; Schreurs, Bernard G.

    2010-01-01

    Previous work has shown high dietary cholesterol can affect learning and memory including rabbit eyeblink conditioning and this effect may be due to increased membrane cholesterol and enhanced hippocampal amyloid beta production. This study investigated whether dietary cholesterol modulates rabbit hippocampal CA1 neuron membrane properties known to be involved in rabbit eyeblink conditioning. Whole-cell current clamp recordings in hippocampal neurons from rabbits fed 2% cholesterol or normal chow for 8 weeks revealed changes including decreased after-hyperpolarization amplitudes (AHPs) – an index of membrane excitability shown to be important for rabbit eyeblink conditioning. This index was reversed by adding copper to drinking water – a dietary manipulation that can retard rabbit eyeblink conditioning. Evidence of cholesterol effects on membrane excitability was provided by application of methyl-β-cyclodextrin, a compound that reduces membrane cholesterol, which increased the excitability of hippocampal CA1 neurons. PMID:20639007

  1. Comparison of High-Density Lipoprotein Cholesterol to Apolipoprotein A-I and A-II to Predict Coronary Calcium and the Effect of Insulin Resistance

    PubMed Central

    Martin, Seth S.; Qasim, Atif N.; Wolfe, Megan; Clair, Caitlin; Schwartz, Stanley; Iqbal, Nayyar; Schutta, Mark; Bagheri, Roshanak; Mehta, Nehal N.; Rader, Daniel J.; Reilly, Muredach P.

    2011-01-01

    High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance. PMID:21257004

  2. Comparison of high-density lipoprotein cholesterol to apolipoprotein A-I and A-II to predict coronary calcium and the effect of insulin resistance.

    PubMed

    Martin, Seth S; Qasim, Atif N; Wolfe, Megan; St Clair, Caitlin; Schwartz, Stanley; Iqbal, Nayyar; Schutta, Mark; Bagheri, Roshanak; Mehta, Nehal N; Rader, Daniel J; Reilly, Muredach P

    2011-02-01

    High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance. PMID:21257004

  3. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

    PubMed Central

    Fernández-Suárez, María E.; Escolà-Gil, Joan C.; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A.; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [3H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  4. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport.

    PubMed

    Fernández-Suárez, María E; Escolà-Gil, Joan C; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  5. Lipoproteins as modulators of atherothrombosis: From endothelial function to primary and secondary coagulation.

    PubMed

    Ouweneel, Amber B; Van Eck, Miranda

    2016-07-01

    Atherothrombosis is a complication of atherosclerosis that causes acute cardiovascular events such as myocardial infarction and stroke. Circulating lipid levels are highly correlated with atherosclerotic plaque development. In addition, experimental evidence suggests that lipids also directly influence thrombosis and influence the risk and the outcome of acute cardiovascular events. Plasma lipoproteins influence three aspects important to atherothrombosis: endothelial function, platelet aggregation (primary coagulation) and secondary coagulation. Overall, VLDL, LDL and oxLDL promote thrombus formation, whereas HDL shows antithrombotic actions. In this review we will address the current knowledge about modulation of atherothrombosis by lipoproteins, summarizing findings from in vitro and in vivo animal studies, as well as from observational and interventional studies in humans. We will conclude with future perspectives for lipid modulation in the prevention of atherothrombosis. PMID:26545626

  6. Central Nervous System Lipoproteins

    PubMed Central

    Mahley, Robert W.

    2016-01-01

    ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease. PMID:27174096

  7. Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection

    PubMed Central

    Sandler, Netanya G.; Zhang, Xinyan; Bosch, Ronald J.; Funderburg, Nicholas T.; Choi, Andrew I.; Robinson, Janet K.; Fine, Derek M.; Coombs, Robert W.; Jacobson, Jeffrey M.; Landay, Alan L.; Douek, Daniel C.; Tressler, Randall; Read, Sarah W.; Wilson, Cara C.; Deeks, Steven G.; Lederman, Michael M.; Gandhi, Rajesh T.

    2014-01-01

    Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)–infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. Clinical Trials Registration. NCT 01543958. PMID:24864123

  8. Impact of hydrogenated fat consumption on endogenous cholesterol synthesis and susceptibility of low-density lipoprotein to oxidation in moderately hypercholesterolemic individuals.

    PubMed

    Cuchel, M; Schwab, U S; Jones, P J; Vogel, S; Lammi-Keefe, C; Li, Z; Ordovas, J; McNamara, J R; Schaefer, E J; Lichtenstein, A H

    1996-02-01

    The effects of replacing corn oil with corn oil margarine in stick form on endogenous cholesterol synthesis and susceptibility of low-density lipoprotein (LDL) to oxidation were assessed in 14 middle-aged and elderly men and women aged 63 +/- 12 years (mean +/- SD) with moderate hypercholesterolemia (mean LDL-cholesterol [LDL-C], 4.24 +/- 0.59 mmol/L at the time of recruitment). Subjects consumed each of two diets for 32-day periods, one enriched in corn oil, which contained 30% of energy as fat (7% saturated fatty acid [SFA], 9% monounsaturated fatty acid [MUFA] [0.4% 18:1n9 trans], and 11% polyunsaturated fatty acid [PUFA]) and 85 mg cholesterol/4.2 MJ, and one enriched in stick corn oil margarine, which contained 30% fat (8% SFA, 12% MUFA [4.2% 18:1n9trans], and 8% PUFA) and 77 mg cholesterol/4.2 MJ. Both diets were isocaloric and supplied by a metabolic research kitchen. Mean total cholesterol levels were lowest (P = .039) when subjects consumed the corn oil-enriched diet (5.01 +/- 0.51 mmol/L) as compared with the margarine-enriched diet (5.30 +/- 0.58 mmol/L). LDL-C levels were 3.24 +/- 0.51 and 3.50 +/- 0.54 mmol/L when subjects consumed corn oil-and margarine-enriched diets, respectively (P = .058). There were no significant differences in high-density lipoprotein cholesterol (HDL-C) or triglyceride concentrations between the two experimental periods. Consumption of the margarine-enriched diet versus the corn oil-enriched diet tended to result in lower cholesterol fractional synthetic rates ([C-FSRs] 0.0466 +/- 0.0175 and 0.0668 +/- 0.0298, respectively, P = .080) and cholesterol absolute synthetic rates ([C-ASRs] 1.1761 +/- 0.5375 and 1.6954 +/- 0.8685, respectively, P = .092); however, differences did not reach statistical significance. Consumption of the margarine-enriched diet versus the corn oil-enriched diet resulted in a significantly higher concentration of alpha-tocopherol in both plasma and LDL(P = .004 and P = .011, respectively). LDL particle

  9. Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein.

    PubMed

    Luthi, Andrea J; Lyssenko, Nicholas N; Quach, Duyen; McMahon, Kaylin M; Millar, John S; Vickers, Kasey C; Rader, Daniel J; Phillips, Michael C; Mirkin, Chad A; Thaxton, C Shad

    2015-05-01

    The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1. PMID:25652088

  10. Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

    PubMed Central

    Luthi, Andrea J.; Lyssenko, Nicholas N.; Quach, Duyen; McMahon, Kaylin M.; Millar, John S.; Vickers, Kasey C.; Rader, Daniel J.; Phillips, Michael C.; Mirkin, Chad A.; Thaxton, C. Shad

    2015-01-01

    The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1. PMID:25652088