Elevation of small, dense low density lipoprotein cholesterol-a possible antecedent of atherogenic lipoprotein phenotype in type 2 diabetes patients in Jos, North-Central Nigeria.

PubMed

Inaku, Kenneth O; Ogunkeye, Obasola O; Abbiyesuku, Fayeofori M; Chuhwak, Evelyn K; Isichei, Christian O; Imoh, Lucius C; Amadu, Noel O; Abu, Alexander O

2017-01-01

The global prevalence of type 2 diabetes is increasing. Dyslipidaemia is a known complication of diabetes mellitus manifesting frequently as cardiovascular diseases and stoke. Elevation of small, dense low density lipoprotein has been recognised as a component of the atherogenic lipoprotein phenotype associated with cardiovascular complications. We speculate that the elevation of this lipoprotein particle may be the antecedent of the atherogenic lipoprotein phenotype. This study therefore aims to determine the pattern of dyslipidaemia among diabetes mellitus patients in Jos, North-Central Nigeria. One hundred and seventy-six patients with type 2 diabetes and 154 age-matched controls were studied. The patients with diabetes were regular clinic attenders and had stable glycaemic control. None were on lipid-lowering therapy. Anthropometric indices, blood pressure, and lipids (including total cholesterol, high density lipoprotein cholesterol, and triglyceride) were measured by chemical methods using the Hitachi 902 analyzer. Low density lipoprotein cholesterol was calculated using the Friedewald's equation. Small, dense low density lipoprotein cholesterol, -sdLDL-C was measured using the precipitation method by Hirano et al. Means of the different groups were compared using EPI Info and a P -value of <0.05 was accepted as significant difference. Total cholesterol, low density lipoprotein cholesterol, triglyceride and small, dense lipoprotein cholesterol were all significantly higher in diabetes patients than controls except high density lipoprotein cholesterol. The percentage of LDL-C as sdLDL-C among the diabetes versus control group was 45% ± 17.79 v 32.0% ± 15.93. Serum sdLDL-C concentration was determined to be 1.45 ± 0.64 among diabetes patients and 0.8 ± 0.54 among control subjects. 75% of diabetes patients had hypertension and were taking blood pressure lowering medications. The classical atherogenic lipoprotein phenotype was not demonstrated

High density lipoprotein cholesterol is associated with serum cortisol in older people.

PubMed

Varma, V K; Rushing, J T; Ettinger, W H

1995-12-01

To determine the associations between serum cortisol and HDL cholesterol, other lipoprotein lipids and cardiovascular risk factors, carotid atherosclerosis, and clinical heart disease in older people. A cross-sectional, observational, ancillary study of the Cardiovascular Health Study (CHS). A total of 245 community-dwelling people, 65 to 89 years old, were recruited consecutively for a 2-month period from the CHS cohort in Forsyth County, North Carolina. Cortisol was measured by radioimmunoassay in serum collected between 7:00 and 10:00 AM after an overnight fast. Cortisol levels were correlated with lipoprotein lipids, insulin, glucose, body mass index, waist-hip ratio, prevalent coronary heart disease, hypertension, diabetes, and carotid atherosclerosis by B-mode ultrasound. Serum cortisol was correlated negatively (r = -.24) with body mass index and waist-hip ratio (r = -.16) but was not related significantly to fasting insulin or glucose. Cortisol was not associated significantly with triglyceride and low density lipoprotein cholesterol but showed a positive correlation (r = .21) with high density lipoprotein cholesterol. The relationship between cortisol and high density lipoprotein cholesterol persisted after adjustment for gender, body mass index, waist-hip ratio, cigarette and alcohol use, triglyceride level, and diabetes. There was a trend toward a negative correlation between cortisol and measures of carotid atherosclerosis, but no significant relationship was indicated between cortisol and prevalent coronary heart disease, hypertension, or diabetes. Endogenous glucocorticoid levels correlated with HDL cholesterol levels and may play a role in the physiologic regulation of high density lipoprotein levels in older people.

Comparison of human plasma low- and high-density lipoproteins as substrates for lecithin: cholesterol acyltransferase.

PubMed

Barter, P J; Hopkins, G J; Gorjatschko, L

1984-01-17

A recent observation that lecithin: cholesterol acyltransferase (EC 2.3.1.43) interacts with both low-density lipoproteins (LDL) and high-density lipoproteins (HDL) in human plasma is in apparent conflict with an earlier finding that the purified enzyme, while highly reactive with isolated HDL, was only minimally reactive with LDL. There is evidence, however, that lecithin: cholesterol acyltransferase may exist physiologically as a component of a complex with other proteins and that studies with the isolated enzyme may therefore provide misleading results. Consequently, interactions of the enzyme with isolated human lipoproteins have been re-examined in incubations containing lecithin: cholesterol acyltransferase as a component of human lipoprotein-free plasma in which a physiologically active complex of the enzyme with other proteins may have been preserved. In this system there was a ready esterification of the free cholesterol associated with both LDL and HDL-subfraction 3 (HDL3) in reactions that obeyed typical enzyme-saturation kinetics. For a given preparation of lipoprotein-free plasma the Vmax values with LDL and with HDL3 were virtually identical. The apparent Km for free cholesterol associated with HDL3 was 5.6 X 10(-5) M, while for that associated with LDL it was 4.1 X 10(-4) M. This implied that, in terms of free cholesterol concentration, the affinity of HDL3 for lecithin: cholesterol acyltransferase was about 7-times greater than that of LDL. When expressed in terms of lipoprotein particle concentration, however, it was apparent that the affinity of LDL for the enzyme was considerably greater than that of HDL3. When the lipoprotein fractions were equated in terms of lipoprotein surface area, the apparent affinities of the two fractions for the enzyme were found to be comparable.

Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.

PubMed

Olson, Eric J; Pearce, Gregory L; Jones, Nigel P; Sprecher, Dennis L

2012-09-01

Peroxisome proliferator-activated receptor-δ-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (-7.3%), triglycerides (-16.9%), apoB (-14.9%), and free fatty acids (-19.4%). The exploratory study showed significant reductions in the concentration of very LDL (-19%), intermediate-density lipoprotein (-52%), and LDL (-14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.

Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake.

PubMed

Friday, K E; Drinkwater, B L; Bruemmer, B; Chesnut, C; Chait, A

1993-12-01

To determine the interactive effects of hormones, exercise, and diet on plasma lipids and lipoproteins, serum estrogen and progesterone levels, nutrient intake, and plasma lipid, lipoprotein, and apolipoprotein concentrations were measured in 24 hypoestrogenic amenorrheic and 44 eumenorrheic female athletes. When compared to eumenorrheic athletes, amenorrheic athletes had higher levels of plasma cholesterol (5.47 +/- 0.17 vs. 4.84 +/- 0.12 mmol/L, P = 0.003), triglyceride (0.75 +/- 0.06 vs. 0.61 +/- 0.03 mmol/L, P = 0.046), low-density lipoprotein (LDL; 3.16 +/- 0.15 vs. 2.81 +/- 0.09 mmol/L, P = 0.037), high-density lipoprotein (HDL; 1.95 +/- 0.07 vs. 1.73 +/- 0.05 mmol/L, P = 0.007), and HDL2 (0.84 +/- 0.06 vs. 0.68 +/- 0.04 mmol/L, P = 0.02) cholesterol. Plasma LDL/HDL cholesterol ratios, very low-density lipoprotein and HDL3 cholesterol, and apolipoprotein A-I and A-II levels were similar in the two groups. Amenorrheic athletes consumed less fat than eumenorrheic subjects (52 +/- 5 vs. 75 +/- 3 g/day, P = 0.02), but similar amounts of calories, cholesterol, protein, carbohydrate, and ethanol. HDL cholesterol levels in amenorrheic subjects correlated positively with the percent of dietary calories from fat (r = 0.42, n = 23, P = 0.045) but negatively with the percent from protein (r = -0.49, n = 23, P = 0.017). Thus, exercise-induced amenorrhea may adversely affect cardiovascular risk by increasing plasma LDL and total cholesterol. However, cardioprotective elevations in plasma HDL and HDL2 cholesterol may neutralize the risk of cardiovascular disease in amenorrheic athletes.

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

USDA-ARS?s Scientific Manuscript database

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...

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, C.H.; Chen, S.M.; Ogle, C.W.

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 inmore » 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.« less

Relationship Between Changes in Serum Thyrotropin and Total and Lipoprotein Cholesterol with Prolonged Antarctic Residence

DTIC Science & Technology

1993-09-01

density lipoprotein ( HDL -C) cholesterol and triglyceride changes in TSH (P < .05)1 TBG (P < .01), TT3 (P < .05), ( TG ), on the other hand, were analyzed from...total thyroxine (TT4), free T4 (FT4), total T3 (TT3), free T3 (FT3), thyroid-binding globulin (TBG), total cholesterol (T-CHOL), high - density lipoprotein ... cholesterol ( HDL -C), triglyceride ( TG ), dietary cholesterol (D-CHOL), dietary fat (D-FAT), and dietary

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.

Relation of Cholesterol and Lipoprotein Parameters with Carotid Artery Plaque Characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study

PubMed Central

Virani, Salim S.; Catellier, Diane J.; Pompeii, Lisa A.; Nambi, Vijay; Hoogeveen, Ron C.; Wasserman, Bruce A.; Coresh, Josef; Mosley, Thomas H.; Otvos, James D.; Sharrett, A. Richey; Boerwinkle, Eric; Ballantyne, Christie M.

2011-01-01

Objective There is a paucity of data regarding relations of apolipoproteins (apolipoprotein B [ApoB] and apolipoprotein A-1 [Apo A-1]), lipoprotein particle measures (low-density lipoprotein particle concentration [LDLp] and high-density lipoprotein particle concentration [HDLp]), and lipoprotein cholesterol measures (low-density lipoprotein cholesterol [LDL-C], non–high-density lipoprotein cholesterol [non– HDL-C], and high-density lipoprotein cholesterol [HDL-C]) with atherosclerotic plaque burden, plaque eccentricity, and lipid-rich core presence as a marker of high-risk plaques. Methods Carotid artery magnetic resonance imaging was performed in 1,670 Atherosclerosis Risk in Communities study participants. Vessel wall and lipid cores were measured; normalized wall index (NWI), standard deviation (SD) of wall thickness (measure of plaque eccentricity) were calculated; and lipid cores were detected in vessels with ≥1.5 mm thickness. Fasting concentrations of cholesterol, ApoB and Apo A-1, and LDLp and HDLp were measured. Results Measures of plaque burden (carotid wall volume, wall thickness, and NWI) were positively associated with atherogenic cholesterol and lipoproteins (p<0.05 for total cholesterol, LDL-C, non–HDL-C, ApoB, and LDLp), but not with HDL-C, Apo A-1, or HDLp. SD of wall thickness was associated with total cholesterol (p 0.01) and non-HDL-C (p 0.02). Although measures of atherogenic or anti-atherogenic cholesterol or lipoprotein were not individually associated with detection of a lipid-rich core, their ratios (total cholesterol/HDL-C, non–HDL-C/ HDL-C, and LDLp/HDLp) were associated with lipid-rich core presence (p≤0.05). Conclusion Extent of carotid atherosclerosis is associated with atherogenic cholesterol and lipoproteins. Atherogenic/anti-atherogenic cholesterol or particle ratios were associated with presence of a detectable lipid-rich core. PMID:21868017

Relation of cholesterol and lipoprotein parameters with carotid artery plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) carotid MRI study.

PubMed

Virani, Salim S; Catellier, Diane J; Pompeii, Lisa A; Nambi, Vijay; Hoogeveen, Ron C; Wasserman, Bruce A; Coresh, Josef; Mosley, Thomas H; Otvos, James D; Sharrett, A Richey; Boerwinkle, Eric; Ballantyne, Christie M

2011-12-01

There is a paucity of data regarding relations of apolipoproteins (apolipoprotein B [ApoB] and apolipoprotein A-1 [Apo A-1]), lipoprotein particle measures (low-density lipoprotein particle concentration [LDLp] and high-density lipoprotein particle concentration [HDLp]), and lipoprotein cholesterol measures (low-density lipoprotein cholesterol [LDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and high-density lipoprotein cholesterol [HDL-C]) with atherosclerotic plaque burden, plaque eccentricity, and lipid-rich core presence as a marker of high-risk plaques. Carotid artery magnetic resonance imaging was performed in 1670 Atherosclerosis Risk in Communities study participants. Vessel wall and lipid cores were measured; normalized wall index (NWI), standard deviation (SD) of wall thickness (measure of plaque eccentricity) were calculated; and lipid cores were detected in vessels with ≥ 1.5mm thickness. Fasting concentrations of cholesterol, ApoB and Apo A-1, and LDLp and HDLp were measured. Measures of plaque burden (carotid wall volume, wall thickness, and NWI) were positively associated with atherogenic cholesterol and lipoproteins (p < 0.05 for total cholesterol, LDL-C, non-HDL-C, ApoB, and LDLp), but not with HDL-C, Apo A-1, or HDLp. SD of wall thickness was associated with total cholesterol (p 0.01) and non-HDL-C (p 0.02). Although measures of atherogenic or anti-atherogenic cholesterol or lipoprotein were not individually associated with detection of a lipid-rich core, their ratios (total cholesterol/HDL-C, non-HDL-C/HDL-C, and LDLp/HDLp) were associated with lipid-rich core presence (p ≤ 0.05). Extent of carotid atherosclerosis is associated with atherogenic cholesterol and lipoproteins. Atherogenic/anti-atherogenic cholesterol or particle ratios were associated with presence of a detectable lipid-rich core. Published by Elsevier Ireland Ltd.

Serum high density lipoprotein cholesterol, alcohol, and coronary mortality in male smokers.

PubMed Central

Paunio, M.; Virtamo, J.; Gref, C. G.; Heinonen, O. P.

1996-01-01

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake. DESIGN--Cohort study. SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland. PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s. MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups. RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward. CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also. PMID:8634563

Total and High-Density Lipoprotein Cholesterol in Adults with Mental Retardation.

ERIC Educational Resources Information Center

Rimmer, James H.; Kelly, Luke E.

1990-01-01

The study evaluated the total cholesterol and high density lipoprotein cholesterol of 40 adults (mean age 37.5 years) with mental retardation residing at an intermediate care facility. Results indicated that 59 percent of the males and 68 percent of the females were at moderate to high risk for coronary heart disease. (DB)

Measurement of low-density lipoprotein cholesterol in assessment and management of cardiovascular disease risk.

PubMed

Jialal, I; Remaley, A T

2014-07-01

The deposition of cholesterol in the arterial wall by the infiltration of low-density lipoproteins (LDLs) is a key step in the development of atherosclerosis. In this Commentary, we discuss recent recommendations for clinical laboratory measurement of low-density lipoprotein cholesterol (LDL-C) and its utility both for assessing cardiovascular disease risk and as a tool in the management of patients receiving lipid-lowering therapy.

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

PubMed

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

2013-08-01

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). Sixth-grade children enrolled in the HEALTHY trial (n = 2384; mean age 11.3 ± 0.6 years; 54.2% female) were evaluated for standard lipids, lipoprotein particles measured by nuclear magnetic resonance, and homeostatic model of insulin resistance. 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. 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 greater body mass index, waist circumference, homeostatic model of insulin resistance, 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. There is as much lipoprotein cholesterol compositional heterogeneity in sixth 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-P burden. Copyright © 2013 Mosby, Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaibelet, Gérald; CEA, SB2SM and UMR8221 CNRS, IBiTec-Saclay, Gif-sur-Yvette; Tercé, François

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 couldmore » 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

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

Comparison of different statin therapy to change low-density lipoprotein cholesterol and high-density lipoprotein cholesterol level in Korean patients with and without diabetes.

PubMed

Khang, Ah Reum; Song, Young Shin; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Jang, Hak Chul; Choi, Sung Hee

2016-01-01

It is difficult to apply the proper intensity of statin for new treatment guidelines in clinical settings because of few data about the statin efficacy in Asians. We conducted a retrospective, observational study to estimate the percentage changes in lipid parameters and glucose induced by different statins. We analyzed 3854 patients including those with nondiabetes and diabetes treated at the outpatient clinic between 2003 and 2013 who were statin-naïve and maintained fixed-dose of statin for at least 18 months. Moderate- and low-intensity statin therapy was effective in reducing low-density lipoprotein cholesterol (LDL-C) to <100 mg/dL (70.3%, 83.0%, and 87.2% of diabetic patients in the low-, moderate-, and high-intensity therapy groups, respectively). The rapid decrease of LDL-C was observed in the first 8 months, and LDL-C-lowering effect was maintained throughout the observation period in even the low-intensity statin group. The effects of statins in elevating high-density lipoprotein cholesterol were similar in each statin groups, except the ezetimibe-simvastatin group (4.5 ± 2.1%) and high-dose atorvastatin groups (9.7 ± 3.3% and 8.7 ± 2.4% for 40 mg and 80 mg of atorvastatin/day, respectively). High-density lipoprotein cholesterol increased less and LDL-C decreased more in diabetes than in nondiabetes. There were no significant changes of fasting glucose after statin use in nondiabetic patients. Moderate- or low-intensity statin was effective enough in reaching National Cholesterol Education Program Adult Treatment Panel III LDL-C target goals in Koreans. Low-intensity statin showed around 30% LDL-C reduction from the baseline level in Koreans, which is comparable to moderate-intensity statin in new guideline. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins.

PubMed

Gillard, Baiba K; Rosales, Corina; Xu, Bingqing; Gotto, Antonio M; Pownall, Henry J

2018-04-12

Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1 -/- mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Cholesterol concentrations in lipoprotein fractions separated by anion-exchange-high-performance liquid chromatography in healthy dogs and dogs with hypercholesterolemia.

PubMed

Oda, Hitomi; Mori, Akihiro; Hirowatari, Yuji; Takoura, Toshie; Manita, Daisuke; Takahashi, Tomoya; Shono, Saori; Onozawa, Eri; Mizutani, Hisashi; Miki, Yohei; Itabashi, Yukiko; Sako, Toshinori

2017-10-01

Anion-exchange (AEX)-high-performance liquid chromatography (HPLC) for measurement of cholesterol can be used to separate serum lipoproteins (high-density lipoprotein (HDL); low-density lipoprotein (LDL); intermediate-density lipoprotein (IDL); very-low-density lipoprotein (VLDL)) in humans. However, AEX-HPLC has not been applied in veterinary practice. We had three objectives: (i) the validation of AEX-HPLC methods including the correlation of serum cholesterol concentration in lipoprotein fraction measured by AEX-HPLC and gel permeation-HPLC (GP-HPLC) in healthy dogs and those with hypercholesterolemia was investigated; (ii) the reference intervals of lipoprotein fractions measured by AEX-HPLC from healthy dogs (n=40) was established; (iii) lipoprotein fractions from the serum of healthy dogs (n=12) and dogs with hypercholesterolemia (n=23) were compared. Analytic reproducibility and precision of AEX-HPLC were acceptable. Positive correlation between serum concentrations of total cholesterol (Total-Chol), HDL cholesterol (HDL-Chol), LDL cholesterol (LDL-Chol)+IDL cholesterol (IDL-Chol), and VLDL cholesterol (VLDL-Chol) was noted for AEX-HPLC and GP-HPLC in healthy dogs and dogs with hypercholesterolemia. Reference intervals measured by AEX-HPLC for serum concentrations of Total-Chol, HDL-Chol, and LDL-Chol were determined to be 2.97-9.32, 2.79-6.57, 0.16-3.28mmol/L (2.5-97.5% interval), respectively. Furthermore, there was significant difference in lipoprotein profiles between healthy and dogs with hypercholesterolemia. These results suggest that AEX-HPLC can be used to evaluate lipoprotein profiles in dogs and could be a new useful indicator of hyperlipidemia in dogs. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Effect of the Probiotic Saccharomyces boulardii on Cholesterol and Lipoprotein Particles in Hypercholesterolemic Adults: A Single-Arm, Open-Label Pilot Study.

PubMed

Ryan, Jennifer Joan; Hanes, Douglas Allen; Schafer, Morgan Beth; Mikolai, Jeremy; Zwickey, Heather

2015-05-01

Elevated blood cholesterol levels are a major risk factor for coronary artery disease, the leading cause of death worldwide. Probiotics have been investigated as potential cholesterol-lowering therapies, but no previous studies have assessed the effect of the probiotic yeast Saccharomyces boulardii on cholesterol levels in human volunteers. The objective of this study was to examine the effect of S. boulardii on serum cholesterol and lipoprotein particles in hypercholesterolemic adults. This study was a single-arm, open-label pilot study. Twelve hypercholesterolemic participants were recruited into the study; one dropped out. Participants took 5.6×10(10) colony forming unit (CFU) encapsulated S. boulardii (Saccharomyces cerevisiae var. boulardii CNCM I-1079) twice daily for an 8-week period. Fasting concentrations of cholesterol (total cholesterol, low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], and triglycerides), lipoprotein particles (very-low-density lipoprotein-particle [VLDL-P], remnant lipoprotein particle [RLP-P], total LDL-P, LDL III-P, LDL IV-P, total HDL-P, and HDL 2b-P), and additional cardiovascular biomarkers (apo B-100, lipoprotein [a], high-sensitivity C-reactive protein, homocysteine, fibrinogen, and insulin) were measured at baseline, after 4 weeks, and after 8 weeks. Remnant lipoprotein particles decreased by 15.5% (p=0.03) over the 8-week period. The remaining outcome measures were not significantly altered. In this pilot study, 8 weeks of daily supplementation with S. boulardii lowered remnant lipoprotein, a predictive biomarker and potential therapeutic target in the treatment and prevention of coronary artery disease.

The association of very-low-density lipoprotein with ankle-brachial index in peritoneal dialysis patients with controlled serum low-density lipoprotein cholesterol level

PubMed Central

2013-01-01

Background Peripheral artery disease (PAD) represents atherosclerotic disease and is a risk factor for death in peritoneal dialysis (PD) patients, who tend to show an atherogenic lipid profile. In this study, we investigated the relationship between lipid profile and ankle-brachial index (ABI) as an index of atherosclerosis in PD patients with controlled serum low-density lipoprotein (LDL) cholesterol level. Methods Thirty-five PD patients, whose serum LDL cholesterol level was controlled at less than 120mg/dl, were enrolled in this cross-sectional study in Japan. The proportions of cholesterol level to total cholesterol level (cholesterol proportion) in 20 lipoprotein fractions and the mean size of lipoprotein particles were measured using an improved method, namely, high-performance gel permeation chromatography. Multivariate linear regression analysis was adjusted for diabetes mellitus and cardiovascular and/or cerebrovascular diseases. Results The mean (standard deviation) age was 61.6 (10.5) years; PD vintage, 38.5 (28.1) months; ABI, 1.07 (0.22). A low ABI (0.9 or lower) was observed in 7 patients (low-ABI group). The low-ABI group showed significantly higher cholesterol proportions in the chylomicron fraction and large very-low-density lipoproteins (VLDLs) (Fractions 3–5) than the high-ABI group (ABI>0.9). Adjusted multivariate linear regression analysis showed that ABI was negatively associated with serum VLDL cholesterol level (parameter estimate=-0.00566, p=0.0074); the cholesterol proportions in large VLDLs (Fraction 4, parameter estimate=-3.82, p=0.038; Fraction 5, parameter estimate=-3.62, p=0.0039) and medium VLDL (Fraction 6, parameter estimate=-3.25, p=0.014); and the size of VLDL particles (parameter estimate=-0.0352, p=0.032). Conclusions This study showed that the characteristics of VLDL particles were associated with ABI among PD patients. Lowering serum VLDL level may be an effective therapy against atherosclerosis in PD patients after the

Balancing Low-density Lipoprotein Cholesterol Reduction and Hepatotoxicity With Lomitapide Mesylate and Mipomersen in Patients With Homozygous Familial Hypercholesterolemia.

PubMed

Won, Jane I; Zhang, Jun; Tecson, Kristen M; McCullough, Peter A

2017-01-01

Homozygous familial hypercholesterolemia (HoFH) is an autosomal codominant disorder manifested by high concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol, and premature cardiovascular disease. Despite conventional lipid-lowering therapy, LDL cholesterol levels remain elevated in patients with HoFH; these patients are considered to be at high risk for cardiovascular events. In 2012-2013, two drugs with novel mechanisms of action were approved by the US Food and Drug Administration for the treatment of HoFH: lomitapide mesylate and mipomersen. Both of these treatments reduce total cholesterol, LDL cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein a, and triglyceride levels. This review describes the clinical tradeoffs in efficacy and hepatotoxicity of these drugs in two cases of HoFH.

Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis

PubMed Central

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

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

Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.

PubMed

Gutierrez, Maria J; Rosenberg, Noah L; Macdougall, Diane E; Hanselman, Jeffrey C; Margulies, Janice R; Strange, Poul; Milad, Mark A; McBride, Scott J; Newton, Roger S

2014-03-01

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

An In-Silico Model of Lipoprotein Metabolism and Kinetics for the Evaluation of Targets and Biomarkers in the Reverse Cholesterol Transport Pathway

PubMed Central

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

2014-01-01

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

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

MicroRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis.

PubMed

Meiler, Svenja; Baumer, Yvonne; Toulmin, Emma; Seng, Kosal; Boisvert, William A

2015-02-01

Macrophage foam cell formation is a key feature of atherosclerosis. Recent studies have shown that specific microRNAs (miRs) are regulated in modified low-density lipoprotein-treated macrophages, which can affect the cellular cholesterol homeostasis. Undertaking a genome-wide screen of miRs regulated in primary macrophages by modified low-density lipoprotein, miR-302a emerged as a potential candidate that may play a key role in macrophage cholesterol homeostasis. The objective of this study was to assess the involvement of miR-302a in macrophage lipid homeostasis and if it can influence circulating lipid levels and atherosclerotic development when it is inhibited in a murine atherosclerosis model. We found that transfection of primary macrophages with either miR-302a or anti-miR-302a regulated the expression of ATP-binding cassette (ABC) transporter ABCA1 mRNA and protein. Luciferase reporter assays showed that miR-302a repressed the 3' untranslated regions (UTR) activity of mouse Abca1 by 48% and human ABCA1 by 45%. In addition, transfection of murine macrophages with miR-302a attenuated cholesterol efflux to apolipoprotein A-1 (apoA-1) by 38%. Long-term in vivo administration of anti-miR-302a to mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) fed an atherogenic diet led to an increase in ABCA1 in the liver and aorta as well as an increase in circulating plasma high-density lipoprotein levels by 35% compared with that of control mice. The anti-miR-302a-treated mice also displayed reduced atherosclerotic plaque size by ≈25% and a more stable plaque morphology with reduced signs of inflammation. These studies identify miR-302a as a novel modulator of cholesterol efflux and a potential therapeutic target for suppressing atherosclerosis. © 2014 American Heart Association, Inc.

Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome.

PubMed

Dokras, Anuja; Playford, Martin; Kris-Etherton, Penny M; Kunselman, Allen R; Stetter, Christy M; Williams, Nancy I; Gnatuk, Carol L; Estes, Stephanie J; Sarwer, David B; Allison, Kelly C; Coutifaris, Christos; Mehta, Nehal; Legro, Richard S

2017-05-01

To study the effects of oral contraceptive pills (OCP), the first-line treatment for PCOS, on high-density lipoprotein cholesterol (HDL-C) function (reverse cholesterol efflux capacity) and lipoprotein particles measured using nuclear magnetic resonance spectroscopy in obese women. Secondary analysis of a randomized controlled trial (OWL-PCOS) of OCP or Lifestyle (intensive Lifestyle modification) or Combined (OCP + Lifestyle) treatment groups for 16 weeks. Eighty-seven overweight/obese women with PCOS at two academic centres. Change in HDL-C efflux capacity and lipoprotein particles. High-density lipoprotein cholesterol efflux capacity increased significantly at 16 weeks in the OCP group [0·11; 95% confidence interval (CI) 0·03, 0·18, P = 0·008] but not in the Lifestyle (P = 0·39) or Combined group (P = 0·18). After adjusting for HDL-C and TG levels, there was significant mean change in efflux in the Combined group (0·09; 95% CI 0·01, 0·15; P = 0·01). Change in HDL-C efflux correlated inversely with change in serum testosterone (r s = -0·21; P = 0·05). In contrast, OCP use induced an atherogenic low-density lipoprotein cholesterol (LDL-C) profile with increase in small (P = 0·006) and large LDL-particles (P = 0·002). Change in small LDL-particles correlated with change in serum testosterone (r s = -0·31, P = 0·009) and insulin sensitivity index (ISI; r s = -0·31, P = 0·02). Both Lifestyle and Combined groups did not show significant changes in the atherogenic LDL particles. Oral contraceptive pills use is associated with improved HDL-C function and a concomitant atherogenic LDL-C profile. Combination of a Lifestyle program with OCP use improved HDL-C function and mitigated adverse effects of OCP on lipoproteins. Our study provides evidence for use of OCP in overweight/obese women with PCOS when combined with Lifestyle changes. © 2017 John Wiley & Sons Ltd.

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux[S

PubMed Central

Meriwether, David; Sulaiman, Dawoud; Wagner, Alan; Grijalva, Victor; Kaji, Izumi; Williams, Kevin J.; Yu, Liqing; Fogelman, Spencer; Volpe, Carmen; Bensinger, Steven J.; Anantharamaiah, G. M.; Shechter, Ishaiahu; Fogelman, Alan M.; Reddy, Srinivasa T.

2016-01-01

The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol. PMID:27199144

Relationship between Icodextrin use and decreased level of small low-density lipoprotein cholesterol fractioned by high-performance gel permeation chromatography

PubMed Central

2013-01-01

Background Because of the absorption of glucose in peritoneal dialysis (PD) solution, PD patients show an atherogenic lipid profile, which is predictive of poor survival in PD patients. Lipoprotein subclasses consist of a continuous spectrum of particles of different sizes and densities (fraction). In this study, we investigated the lipoprotein fractions in PD patients with controlled serum low-density lipoprotein (LDL) cholesterol level, and evaluated the effects of icodextrin on lipid metabolism. Methods Forty-nine PD patients were enrolled in this cross-sectional study in Japan. The proportions of cholesterol levels to total cholesterol level (cholesterol proportion) in 20 lipoprotein fractions were measured using an improved method of high-performance gel permeation chromatography (HPGPC). Results Twenty-six patients used icodextrin. Although no significant differences in cholesterol levels in LDL and high-density lipoprotein (HDL) were observed between the patients using icodextrin (icodextrin group) and control groups, HPGPC showed that the icodextrin group had significantly lower cholesterol proportions in the small LDL (t-test, p=0.053) and very small LDL (p=0.019), and significantly higher cholesterol proportions in the very large HDL and large HDL than the control group (p=0.037; p=0.066, respectively). Multivariate analysis adjusted for patient characteristics and statin use showed that icodextrin use was negatively associated with the cholesterol proportions in the small LDL (p=0.037) and very small LDL (p=0.026), and positively with those in the very large HDL (p=0.040), large HDL (p=0.047), and medium HDL (p=0.009). Conclusions HPGPC showed the relationship between icodextrin use and the cholesterol proportions in lipoprotein fractions in PD patients. These results suggest that icodextrin may improve atherogenic lipid profiles in a manner different from statin. PMID:24161017

Serum LDL cholesterol concentration and lipoprotein electrophoresis pattern in patients with small cell lung cancer.

PubMed

Siemianowicz, K; Gminski, J; Stajszczyk, M; Wojakowski, W; Goss, M; Machalski, M; Telega, A; Brulinski, K; Magiera-Molendowska, H

2000-01-01

Epidemiological studies show that people with low level of total cholesterol have a greater risk of death due to cancer, predominantly lung cancer. The aim of our study was to evaluate serum level of LDL cholesterol and lipoprotein electrophoresis pattern in patients with small cell lung cancer and their dependence on clinical stage of the neoplasm. The studied group consisted of 34 patients with newly diagnosed small cell lung cancer and 39 healthy controls. Fasting level of LDL cholesterol was analyzed and lipoprotein electrophoresis was performed. There were no statistically significant differences of evaluated serum lipid parameters between lung cancer patients and controls, and between the clinical stages of small cell lung cancer.

Non-high-density lipoprotein cholesterol: an important predictor of stroke and diabetes-related mortality in Japanese elderly diabetic patients.

PubMed

Araki, Atsushi; Iimuro, Satoshi; Sakurai, Takashi; Umegaki, Hiroyuki; Iijima, Katsuya; Nakano, Hiroshi; Oba, Kenzo; Yokono, Koichi; Sone, Hirohito; Yamada, Nobuhiro; Ako, Junya; Kozaki, Koichi; Miura, Hisayuki; Kashiwagi, Atsunori; Kikkawa, Ryuichi; Yoshimura, Yukio; Nakano, Tadasumi; Ohashi, Yasuo; Ito, Hideki

2012-04-01

To evaluate the association of low-density lipoprotein, high-density lipoprotein and non-high-density lipoprotein cholesterol with the risk of stroke, diabetes-related vascular events and mortality in elderly diabetes patients. This study was carried out as a post-hoc landmark analysis of a randomized, controlled, multicenter, prospective intervention trial. We included 1173 elderly type 2 diabetes patients (aged ≥ 65 years) from 39 Japanese institutions who were enrolled in the Japanese elderly diabetes intervention trial study and who could be followed up for 1 year. A landmark survival analysis was carried out in which follow up was set to start 1 year after the initial time of entry. During 6 years of follow up, there were 38 cardiovascular events, 50 strokes, 21 diabetes-related deaths and 113 diabetes-related events. High low-density lipoprotein cholesterol was associated with incident cardiovascular events, and high glycated hemoglobin was associated with strokes. After adjustment for possible covariables, non-high-density lipoprotein cholesterol showed a significant association with increased risk of stroke, diabetes-related mortality and total events. The adjusted hazard ratios (95% confidence intervals) of non-high-density lipoprotein cholesterol were 1.010 (1.001-1.018, P = 0.029) for stroke, 1.019 (1.007-1.031, P < 0.001) for diabetes-related death and 1.008 (1.002-1.014; P < 0.001) for total diabetes-related events. Higher non-high-density lipoprotein cholesterol was associated with an increased risk of stroke, diabetes-related mortality and total events in elderly diabetes patients. © 2012 Japan Geriatrics Society.

Cholesterol-lowering activity of plant sterol-egg yolk lipoprotein complex in rats.

PubMed

Matsuoka, Ryosuke; Muto, Ayano; Kimura, Mamoru; Hoshina, Ryosuke; Wakamatsu, Toshio; Masuda, Yasunobu

2008-01-01

Free plant sterols cannot be dissolved in oil or water. Using free plant sterols and egg yolks, we developed a plant sterol-egg yolk lipoprotein complex (PSY) that can be dispersed in water and considered suitable for use in processed foods. The cholesterol-lowering activity of PSY was equal to that of free plant sterols and plant sterol esters. Consumption of a freeze-dried PSY-containing omelet reduced serum and hepatic cholesterol concentrations. The results suggest that PSY has cholesterol-lowering activity equivalent to that of free plant sterols and plant sterol esters. Moreover, the cholesterol-lowering activity of PSY was maintained in processed foods.

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

USDA-ARS?s Scientific Manuscript database

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...

Drugs targeting high-density lipoprotein cholesterol for coronary artery disease management.

PubMed

Katz, Pamela M; Leiter, Lawrence A

2012-01-01

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Assembly of high-density lipoprotein.

PubMed

Yokoyama, Shinji

2006-01-01

Mammalian somatic cells do not catabolize cholesterol and need to export it for its homeostasis at the levels of cells and whole bodies. This reaction may reduce intracellularly accumulated cholesterol in excess and would contribute to prevention or regression of the initial stage of atherosclerosis. High-density lipoprotein (HDL) is thought to play a main role in this reaction, and 2 independent mechanisms are proposed for this reaction. First, cholesterol is exchanged in a nonspecific physicochemical manner between cell surface and extracellular lipoproteins, and cholesterol esterification on HDL provides a driving force for net removal of cell cholesterol. Second, apolipoproteins directly interact with cells and generate HDL by removing cellular phospholipid and cholesterol. This reaction is a major source of plasma HDL and is mediated by a membrane protein, ABCA1. Lipid-free or lipid-poor helical apolipoproteins primarily recruit cellular phospholipid to assemble HDL particles, and cholesterol enrichment in these particles is regulated independently. ABCA1 is a rate-limiting factor of the HDL assembly and is regulated by transcriptional factors and posttranscriptional factors. Posttranscriptional regulation of ABCA1 includes modulation of its calpain-mediated degradation.

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

Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial.

PubMed

Chinwong, Surarong; Chinwong, Dujrudee; Mangklabruks, Ampica

2017-01-01

This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18-25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results . Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL ( p = 0.001) compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion . Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported.

Daily Consumption of Virgin Coconut Oil Increases High-Density Lipoprotein Cholesterol Levels in Healthy Volunteers: A Randomized Crossover Trial

PubMed Central

2017-01-01

This open-label, randomized, controlled, crossover trial assessed the effect of daily virgin coconut oil (VCO) consumption on plasma lipoproteins levels and adverse events. The study population was 35 healthy Thai volunteers, aged 18–25. At entry, participants were randomly allocated to receive either (i) 15 mL VCO or (ii) 15 mL 2% carboxymethylcellulose (CMC) solution (as control), twice daily, for 8 weeks. After 8 weeks, participants had an 8-week washout period and then crossed over to take the alternative regimen for 8 weeks. Plasma lipoproteins levels were measured in participants at baseline, week-8, week-16, and week-24 follow-up visits. Results. Of 32 volunteers with complete follow-up (16 males and 16 females), daily VCO intake significantly increased high-density lipoprotein cholesterol by 5.72 mg/dL (p = 0.001) compared to the control regimen. However, there was no difference in the change in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels between the two regimens. Mild diarrhea was reported by some volunteers when taking VCO, but no serious adverse events were reported. Conclusion. Daily consumption of 30 mL VCO in young healthy adults significantly increased high-density lipoprotein cholesterol. No major safety issues of taking VCO daily for 8 weeks were reported. PMID:29387131

Cholesterol lipoproteins and prevalence of dyslipidemias in urban Asian Indians: A cross sectional study

PubMed Central

Guptha, Soneil; Gupta, Rajeev; Deedwania, Prakash; Bhansali, Anil; Maheshwari, Anuj; Gupta, Arvind; Gupta, Balkishan; Saboo, Banshi; Singh, Jitendra; Achari, Vijay; Sharma, Krishna Kumar

2014-01-01

Objective To determine levels of cholesterol lipoproteins and prevalence of dyslipidemias in urban Asian Indians. Methods Population based 6123 subjects (men 3388) were evaluated. Mean±1SD of various cholesterol lipoproteins (total, HDL, LDL and non-HDL cholesterol) and triglycerides were reported. Subjects were classified according to US National Cholesterol Education Program. Results Age-adjusted levels in men and women were cholesterol total 178.4 ± 39 and 184.6 ± 39, HDL 44.9 ± 11 and 51.1 ± 11, LDL 102.5 ± 33 and 106.2 ± 33, total:HDL 4.15 ± 1.2 and 3.79 ± 1.0 and triglycerides 162.5 ± 83 and 143.7 ± 83 mg/dl. Age-adjusted prevalence (%) in men and women, respectively were, total cholesterol ≥200 mg/dl 25.1 and 24.9, LDL cholesterol ≥130 mg/dl 16.3 and 15.1 and ≥100 mg/dl 49.5 and 49.7, HDL cholesterol <40/<50 mg/dl 33.6 and 52.8, total:HDL cholesterol ≥4.5 29.4 and 16.8, and triglycerides ≥150 mg/dl 42.1 and 32.9%. Cholesterol level was significantly greater in subjects with better socioeconomic status, body mass index and waist circumference while triglycerides were more among those with high socioeconomic status, fat intake, body mass index and waist circumference (p < 0.05). Hypercholesterolemia awareness (15.6%), treatment (7.2%) and control (4.1%) were low. Conclusions Mean cholesterol and LDL cholesterol are low and triglycerides were high in urban Asian Indians. Most prevalent dyslipidemias are borderline high LDL, low HDL and high triglycerides. Subjects with high socioeconomic status, high fat intake and greater adiposity have higher total and LDL cholesterol and triglyceride and lower HDL cholesterol. PMID:24973832

Novel nonstatin strategies to lower low-density lipoprotein cholesterol.

PubMed

Davidson, Michael H

2009-01-01

There remains an unmet need to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients who are maximized on current therapy or intolerant to statins. Several novel agents have been developed to lower LDL-C, either as monotherapy or in combination with statins. These novel therapies include squalene synthase inhibitors, microsomal triglyceride transfer protein inhibitors, and antisense apolipoprotein B. Although each of these novel therapies effectively lowers LDL-C, challenges remain in the clinical development to assess long-term safety.

A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

PubMed Central

Calabuig-Navarro, M. V.; Jackson, K. G.; Kemp, C. F.; Leake, D. S.; Walden, C. M.; Lovegrove, J. A.; Minihane, A. M.

2017-01-01

At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4–6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482. PMID:28276521

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

The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis.

PubMed

Hennuyer, Nathalie; Duplan, Isabelle; Paquet, Charlotte; Vanhoutte, Jonathan; Woitrain, Eloise; Touche, Véronique; Colin, Sophie; Vallez, Emmanuelle; Lestavel, Sophie; Lefebvre, Philippe; Staels, Bart

2016-06-01

Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[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.

Higher high-density lipoprotein cholesterol in African-American women with polycystic ovary syndrome compared with Caucasian counterparts.

PubMed

Koval, Kathryn W; Setji, Tracy L; Reyes, Eric; Brown, Ann J

2010-09-01

Studies have demonstrated lipid differences among African-Americans and Caucasians and between women with polycystic ovary syndrome (PCOS) and normally ovulating women. However, few studies have examined racial differences in lipoprotein levels in women with PCOS. This study compared lipoprotein levels in African-American and Caucasian women with PCOS. We performed a retrospective chart review of 398 subjects seen as new patients for PCOS at the Duke University Medical Center Endocrinology Clinic in Durham, NC. We identified 126 charts appropriate for review, based on a diagnosis of PCOS (using the 1990 National Institutes of Health criteria), a self-reported race of either Caucasian or African-American, and a body mass index (BMI) higher than 25. We excluded patients taking glucophage, oral contraceptives, or lipid-lowering medications. Age, BMI, total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, random triglycerides (TG), and oral glucose tolerance test measurements were collected and included in the analysis. African-American women with PCOS had higher HDL cholesterol levels (52.6 vs. 47.5 mg/dl, P = 0.019), lower non-HDL cholesterol (134.1 vs. 154.6 mg/dl, P = 0.046), and lower TG levels (97.5 vs. 168.2 mg/dl, P < 0.001) than Caucasian women. These differences could not be attributed to age, BMI, or differences in insulin resistance as determined by homeostasis model assessment of insulin resistance. African-American women with PCOS appear to have a more favorable lipid profile than Caucasian women with PCOS having higher HDL cholesterol, lower non-HDL cholesterol, and lower TG when BMI and insulin resistance are equal.

Lipoprotein degradation and cholesterol esterification in primary cell cultures of rabbit atherosclerotic lesions.

PubMed Central

Jaakkola, O.; Nikkari, T.

1990-01-01

Lipoprotein metabolism and cholesterol accumulation in atherosclerotic lesions was studied using enzymatically isolated primary cell cultures from aortas of rabbits made atherosclerotic by cholesterol feeding. The cultures consisted of macrophages and smooth muscle cells, thus resembling, in composition, fatty streak lesions. The mean (+/- SD) cholesteryl ester content of the dispersed cells was 1059 +/- 445 micrograms/mg cell protein, but it declined steeply during 1 week in primary culture. The uptake of low-density lipoprotein (LDL), beta-migrating very low-density lipoprotein (beta-VLDL), and acetylated LDL (acetyl-LDL), labeled with 125I or with the fluorescent probe 1,1'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine (DiI), was studied in 2-day-old primary cultures. DiI-acetyl-LDL was avidly taken up by the macrophages and, to a lesser extent, by some smooth muscle cells. The uptake of DiI-beta-VLDL by the macrophages was weaker and less homogeneous than that of DiI-acetyl-LDL. The degradation rates of 125I-labeled beta-VLDL, LDL and acetyl-LDL were 135 +/- 54, 195 +/- 20, and 697 +/- 14 ng/mg cell protein/8 hours, respectively. Incubation with unlabeled acetyl-LDL enhanced the incorporation of [3H]oleate into cholesteryl esters and increased the cellular cholesteryl ester content. These results suggest that arterial macrophages and, to some extent, smooth muscle cells from cholesterol-fed rabbits actively metabolize acetyl-LDL and are thus capable of accumulating cholesteryl esters by uptake of modified forms of LDL. Images Figure 2 PMID:2201201

Threshold level or not for low-density lipoprotein cholesterol.

PubMed

Barter, P J; Sacks, F M

2001-05-01

As drugs, such as the statins, and other therapies demonstrate the ability to significantly lower levels of low-density lipoprotein cholesterol (LDL-C), one issue is whether there is a lower threshold below which no further decline in coronary heart disease occurs. Those who evaluate the data from multiple trials and conclude that no significant decrease in coronary event rates occurs at or below 125 mg/dL suggest using this level as a guideline for clinical application of cholesterol-lowering therapy. On the other hand, analysis of the results of the same population and primary prevention studies concludes that no such threshold exists. The issues affected by the decision of whether to use a threshold include costs to the healthcare system for additional physician time, tests, and medication; unknown clinical events and safety related to very low LDL-C; and resource prioritization to an unestablished therapeutic approach.

Oxidative tyrosylation of high density lipoprotein by peroxidase enhances cholesterol removal from cultured fibroblasts and macrophage foam cells.

PubMed Central

Francis, G A; Mendez, A J; Bierman, E L; Heinecke, J W

1993-01-01

Lipoprotein oxidation is thought to play a pivotal role in atherogenesis, yet the underlying reaction mechanisms remain poorly understood. We have explored the possibility that high density lipoprotein (HDL) might be oxidized by peroxidase-generated tyrosyl radical. Exposure of HDL to L-tyrosine, H2O2, and horseradish peroxidase crosslinked its apolipoproteins and strikingly increased protein-associated fluorescence. The reaction required L-tyrosine but was independent of free metal ions; it was blocked by either catalase or the heme poison aminotriazole. Dityrosine and other tyrosine oxidation products were detected in the apolipoproteins of HDL modified by the peroxidase/L-tyrosine/H2O2 system, implicating tyrosyl radical in the reaction pathway. Further evidence suggests that tyrosylated HDL removes cholesterol from cultured cells more effectively than does HDL. Tyrosylated HDL was more potent than HDL at inhibiting cholesterol esterification by the acyl-CoA:cholesterol acyltransferase reaction, stimulating the incorporation of [14C]acetate into [14C]cholesterol, and depleting cholesteryl ester stores in human skin fibroblasts. Moreover, exposure of mouse macrophage foam cells to tyrosylated HDL markedly diminished cholesteryl ester and free cholesterol mass. We have recently found that myeloperoxidase, a heme protein secreted by activated phagocytes, can also convert L-tyrosine to o,o'-dityrosine. This raises the possibility that myeloperoxidase-generated tyrosyl radical may modify HDL, enabling the lipoprotein to protect the artery wall against pathological cholesterol accumulation. Images Fig. 1 PMID:8341680

Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk?

PubMed

Dean, Bonnie B; Borenstein, Jeff E; Henning, James M; Knight, Kevin; Merz, C Noel Bairey

2004-06-01

The cardiovascular risk reduction observed in many trials of lipid-lowering agents is greater than expected on the basis of observed low-density lipoprotein cholesterol (LDL-C) level reductions. Our objective was to explore the degree to which high-density lipoprotein cholesterol (HDL-C) level changes explain cardiovascular risk reduction. A systematic review identified trials of lipid-lowering agents reporting changes in HDL-C and LDL-C levels and the incidence of coronary heart disease (CHD). The observed relative risk reduction (RRR) in CHD morbidity and mortality rates was calculated. The expected RRR, given the treatment effect on total cholesterol level, was calculated for each trial with logistic regression coefficients from observational studies. The difference between observed and expected RRR was plotted against the change in HDL-C level, and a least-squares regression line was calculated. Fifty-one trials were identified. Nineteen statin trials addressed the association of HDL-C with CHD. Limited numbers of trials of other therapies precluded additional analyses. Among statin trials, therapy reduced total cholesterol levels as much as 32% and LDL-C levels as much as 45%. HDL-C level increases were <10%. Treatment effect on HDL-C levels was not a significant linear predictor of the difference in observed and expected CHD mortality rates, although we observed a trend in this direction (P =.08). Similarly, HDL-C effect was not a significant linear predictor of the difference between observed and expected RRRs for CHD morbidity (P =.20). Although a linear trend toward greater risk reduction was observed with greater effects on HDL-C, differences were not statistically significant. The narrow range of HDL-C level increases in the statin trials likely reduced our ability to detect a beneficial HDL-C effect, if present.

The Ratio of Unesterified/esterified Cholesterol is the Major Determinant of Atherogenicity of Lipoprotein Fractions.

PubMed

Bagheri, Babak; Alikhani, Asal; Mokhtari, Hossein; Rasouli, Mehdi

2018-04-01

The hypothesis is proposed that the atherogenicity of lipoporotein fractions is correlated with the content of unesterified cholesterol. To evaluate the role and prognostic values of unesterified and esterified cholesterol in lipoprotein fractions for coronary artery disease (CAD). The study population consisted of 400 patients who were divided to CAD controls and cases according to the data of coronary angiography. Fractional cholesterol esterification (FCE) as well as the complete profile of lipids and (apo)lipoproteins were determined. Total cholesterol was increased significantly in CAD patients (196.3 ± 52.3 mg/dL vs. 185.7 ± 48.0, p≤ 0.049) and the increment occurred totally in unesterified portion (77.2 ± 28.4 mg/dL vs. 71.1 ± 24.4, p≤ 0.031). HDL cholesterol showed a significant decrease in CAD group (39.9 ± 9.5 mg/dL vs. 44.6 ± 10.5, p≤ 0.001), but the decrement occurred wholly in the esterified portion (26.2 ± 9.2 mg/dL vs. 31.1 ± 8.1, p≤ 0.001). NonHDL cholesterol was increased significantly in CAD group (156.8 ± 48.3 mg/dL vs. 140.3 ± 43.6, p≤ 0.001), and the changes occurred in both un- and esterified portions. FCE in HDL was diminished significantly in CAD patients (64.8 ± 13.9% vs. 69.3 ± 7.9, p≤ 0.01). In multivariate logistic regression analysis, unesterified cholesterol in NonHDL (UeNonHDLc) and esterified cholesterol in HDL (EsHDLc) excluded total cholesterol and HDLc respectively from the regression equation. In ROC analysis, the ratio of UeNonHDLc/EsHDLc was the strongest predictor for CAD among cholesterol subfractions. The results confirm that UeNonHDLc is atherogenic and EsHDLc is antiatherogenic and are independent risk factors for CAD.

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

USDA-ARS?s Scientific Manuscript database

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...

Prevalence of Low High-density Lipoprotein Cholesterol Among Adults, by Physical Activity: United States, 2011-2014.

PubMed

Zwald, Marissa L; Akinbami, Lara J; Fakhouri, Tala H I; Fryar, Chryl D

2017-03-01

Data from the National Health and Nutrition Examination Survey •The prevalence of low high-density lipoprotein (HDL) cholesterol was significantly higher among adults who did not meet recommended physical activity guidelines (21.0%) than adults who met the guidelines (17.7%). •Low HDL cholesterol prevalence differed significantly for both men and women by adherence to physical activity guidelines. •Prevalence of low HDL cholesterol declined as age increased for both those who did and did not meet the physical activity guidelines. •Non-Hispanic white and non-Hispanic black adults who did not meet the physical activity guidelines had a higher prevalence than those who met the guidelines. •Low HDL cholesterol prevalence declined with increasing education level regardless of adherence to physical activity guidelines. Regular physical activity can improve cholesterol levels among adults, including increasing high-density lipoprotein (HDL) cholesterol (1). HDL cholesterol is known as "good" cholesterol because high levels can reduce cardiovascular disease risk (2). The 2008 Physical Activity Guidelines for Americans recommend that adults engage in 150 minutes or more of moderate-intensity aerobic activity per week, 75 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination (3). Adherence to these guidelines is expected to decrease the prevalence of low HDL cholesterol levels (4-8). This report presents national data for 2011-2014 on low HDL cholesterol prevalence among U.S. adults aged 20 and over, by whether they met these guidelines. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Small, qualitative changes in fatty acid intake decrease plasma low-density lipoprotein-cholesterol levels in mildly hypercholesterolemic outpatients on their usual high-fat diets.

PubMed

Lecerf, Jean-Michel; Luc, Gérald; Marécaux, Nadine; Bal, Sylvie; Bonte, Jean-Paul; Lacroix, Brigitte; Cayzeele, Amélie

2009-01-01

The diet is the first step in managing hypercholesterolemia. The objective of the present study is to assess whether moderate changes in dietary fatty acids improve plasma lipid parameters in mildly hypercholesterolemic outpatients. Using a randomized double-blind study, 121 outpatients within two groups received an isocaloric amount of unsaturated margarine or butter. Clinical and anthropometric measurements and a 3-day food record were made. Chi-square and Fisher's tests were used to compare qualitative variables and the general linear procedure was used to compare the groups. Additional analyses were performed after adjustment. There was a significant difference (P <0.03) in low-density lipoprotein-cholesterol levels between the groups. Total cholesterol, low-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol and apolipoprotein B values decreased in the unsaturated group in comparison with the saturated group. Low-density lipoprotein-cholesterol changes were correlated with the variation in polyunsaturated fatty acid intake and with plasma phospholipid linoleic acid levels. A small change in saturated by polyunsaturated fatty acid intake may improve plasma lipid parameters in mildly hypercholesterolemic subjects.

HDL: The "Good" Cholesterol

MedlinePlus

... and LDL (bad) cholesterol: HDL stands for high-density lipoproteins. It is called the "good" cholesterol because ... cholesterol from your body. LDL stands for low-density lipoproteins. It is called the "bad" cholesterol because ...

LDL: The "Bad" Cholesterol

MedlinePlus

... and HDL (good) cholesterol: LDL stands for low-density lipoproteins. It is called the "bad" cholesterol because ... cholesterol in your arteries. HDL stands for high-density lipoproteins. It is called the "good" cholesterol because ...

Phospholipase A2-treated human high-density lipoprotein and cholesterol movements: exchange processes and lecithin: cholesterol acyltransferase reactivity.

PubMed

Chollet, F; Perret, B P; Chap, H; Douste-Blazy, L

1986-02-12

Human HDL3 (d 1.125-1.21 g/ml) were treated by an exogenous phospholipase A2 from Crotalus adamenteus in the presence of albumin. Phosphatidylcholine hydrolysis ranged between 30 and 90% and the reisolated particle was essentially devoid of lipolysis products. (1) An exchange of free cholesterol was recorded between radiolabelled erythrocytes at 5-10% haematocrit and HDL3 (0.6 mM total cholesterol) from 0 to 12-15 h. Isotopic equilibration was reached. Kinetic analysis of the data indicated a constant rate of free cholesterol exchange of 13.0 microM/h with a half-time of equilibration around 3 h. Very similar values of cholesterol exchange, specific radioactivities and kinetic parameters were measured when phospholipase-treated HDL replaced control HDL. (2) The lecithin: cholesterol acyltransferase reactivity of HDL3, containing different amounts of phosphatidylcholine, as achieved by various degrees of phospholipase A2 treatment, was measured using a crude preparation of lecithin: cholesterol acyltransferase (the d 1.21-1.25 g/ml plasma fraction). The rate of esterification was determined between 0 and 12 h. Following a 15-30% lipolysis, the lecithin: cholesterol acyltransferase reactivity of HDL3 was reduced about 30-40%, and then continued to decrease, though more slowly, as the phospholipid content was further lowered in the particle. (3) The addition of the lecithin: cholesterol acyltransferase preparation into an incubation medium made of labelled erythrocytes and HDL3 promoted a movement of radioactive cholesterol out of cells, above the values of exchange, and an accumulation of cholesteryl esters in HDL. This reflected a mass consumption of free cholesterol, from both the cellular and the lipoprotein compartments upon the lecithin: cholesterol acyltransferase action. As a consequence of a decreased reactivity, phospholipase-treated HDL (with 2/3 of phosphatidylcholine hydrolyzed) proved much less effective in the lecithin: cholesterol acyltransferase

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

USDA-ARS?s Scientific Manuscript database

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...

Levels of high-density lipoprotein cholesterol (HDL-C) among children with steady-state sickle cell disease

PubMed Central

2010-01-01

Background The search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis. Methods We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. Results Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis. Conclusions We hypothesize that some SCD patients can have a specific dyslipidemic

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

PubMed Central

Aslibekyan, Stella; Straka, Robert J.; Irvin, Marguerite R.; Claas, Steven A.; Arnett, Donna K.

2017-01-01

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 genes have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts. PMID:23469915

Interaction of high density lipoprotein particles with membranes containing cholesterol.

PubMed

Sanchez, Susana A; Tricerri, Maria A; Gratton, Enrico

2007-08-01

In this study, free cholesterol (FC) efflux mediated by human HDL was investigated using fluorescence methodologies. The accessibility of FC to HDL may depend on whether it is located in regions rich in unsaturated phospholipids or in domains containing high levels of FC and sphingomyelin, known as "lipid rafts." Laurdan generalized polarization and two-photon microscopy were used to quantify FC removal from different pools in the bilayer of giant unilamellar vesicles (GUVs). GUVs made of POPC and FC were observed after incubation with reconstituted particles containing apolipoprotein A-I and POPC [78A diameter reconstituted high density lipoprotein (rHDL)]. Fluorescence correlation spectroscopy data show an increase in rHDL size during the incubation period. GUVs made of two "raft-like" mixtures [DOPC/DPPC/FC (1:1:1) and POPC/SPM/FC (6:1:1)] were used to model liquid-ordered/liquid-disordered phase coexistence. Through these experiments, we conclude that rHDL preferentially removes cholesterol from the more fluid phases. These data, and their extrapolation to in vivo systems, show the significant role that phase separation plays in the regulation of cholesterol homeostasis.

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects.

PubMed

Leança, Camila C; Nunes, Valéria S; Panzoldo, Natália B; Zago, Vanessa S; Parra, Eliane S; Cazita, Patrícia M; Jauhiainen, Matti; Passarelli, Marisa; Nakandakare, Edna R; de Faria, Eliana C; Quintão, Eder C R

2013-11-22

We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-₁HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-₁HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

Effect of exercise training on plasma levels and functional properties of high-density lipoprotein cholesterol in the metabolic syndrome.

PubMed

Casella-Filho, Antonio; Chagas, Antonio Carlos P; Maranhão, Raul C; Trombetta, Ivani C; Cesena, Fernando H Y; Silva, Vanessa M; Tanus-Santos, Jose Eduardo; Negrão, Carlos E; da Luz, Protasio L

2011-04-15

Intense lifestyle modifications can change the high-density lipoprotein (HDL) cholesterol concentration. The aim of the present study was to analyze the early effects of short-term exercise training, without any specific diet, on the HDL cholesterol plasma levels and HDL functional characteristics in patients with the metabolic syndrome (MS). We studied 30 sedentary subjects, 20 with and 10 without the MS. The patients with the MS underwent moderate intensity exercise training for 3 months on bicycle ergometers. Blood was sampled before and after training for biochemical analysis, paraoxonase-1 activity, and HDL subfraction composition and antioxidative capacity. Lipid transfer to HDL was assayed in vitro using a labeled nanoemulsion as the lipid donor. At baseline, the MS group had greater triglyceride levels and a lower HDL cholesterol concentration and lower paraoxonase-1 activity than did the controls. Training decreased the plasma triglycerides but did not change the low-density lipoprotein or HDL cholesterol levels. Nonetheless, exercise training increased the HDL subfractions' antioxidative capacity and paraoxonase-1 activity. After training, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL, reaching normal values. In conclusion, the present investigation has added relevant information about the dissociation between the quantitative and qualitative aspects of HDL after short-term exercise training without any specific diet in those with the MS, highlighting the importance of evaluating the functional aspects of the lipoproteins, in addition to their plasma levels. Copyright © 2011 Elsevier Inc. All rights reserved.

The Relationship between the Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Metabolic Syndrome.

PubMed

Shin, Hyun-Gyu; Kim, Young-Kwang; Kim, Yong-Hwan; Jung, Yo-Han; Kang, Hee-Cheol

2017-11-01

Metabolic syndrome is associated with cardiovascular diseases and is characterized by insulin resistance. Recent studies suggest that the triglyceride/high-density lipoprotein cholesterol (TG/HDLC) ratio predicts insulin resistance better than individual lipid levels, including TG, total cholesterol, low-density lipoprotein cholesterol (LDLC), or HDLC. We aimed to elucidate the relationship between the TG/HDLC ratio and metabolic syndrome in the general Korean population. We evaluated the data of adults ≥20 years old who were enrolled in the Korean National Health and Nutrition Examination Survey in 2013 and 2014. Subjects with angina pectoris, myocardial infarction, stroke, or cancer were excluded. Metabolic syndrome was defined by the harmonized definition. We examined the odds ratios (ORs) of metabolic syndrome according to TG/HDLC ratio quartiles using logistic regression analysis (SAS ver. 9.4; SAS Institute Inc., Cary, NC, USA). Weighted complex sample analysis was also conducted. We found a significant association between the TG/HDLC ratio and metabolic syndrome. The cutoff value of the TG/HDLC ratio for the fourth quartile was ≥3.52. After adjustment, the OR for metabolic syndrome in the fourth quartile compared with that of the first quartile was 29.65 in men and 20.60 in women (P<0.001). The TG/HDLC ratio is significantly associated with metabolic syndrome.

Relationship between lipoprotein subfraction cholesterol and residual risk for cardiovascular outcomes: A post hoc analysis of the AIM-HIGH trial.

PubMed

Toth, Peter P; Jones, Steven R; Slee, April; Fleg, Jerome; Marcovina, Santica M; Lacy, Megan; McBride, Ruth; Boden, William E

2018-03-09

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial failed to demonstrate incremental clinical benefit of extended-release niacin (ERN) in 3414 statin-treated patients with established cardiovascular (CV) disease who had low baseline levels of high-density lipoprotein cholesterol (HDL-C) as compared to placebo. A previous secondary analysis suggested that ERN provided outcome benefits in ERN-treated patients with high triglycerides (TGs; >200 mg/dL) and very low HDL-C (<32 mg/dL) at baseline. The current analysis sought to ascertain how changes in TG-enriched lipoproteins and HDL subfractions impact residual risk in the comparator treatment arms. We evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and CV outcomes in a non-prespecified, post hoc analysis of the AIM-HIGH trial. Lipoprotein subfraction analysis was performed with zonal ultracentrifugation in 2457 AIM-HIGH participants at baseline and 1 year of treatment. Hazard ratios were estimated using Cox proportional hazards models for relationships between lipoproteins and the composite primary endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Analyses were performed for the entire cohort and in participants with TGs > 200 mg/dL and HDL-C < 32 mg/dL. Apoprotein B-containing lipoproteins and their subfractions decreased significantly in both treatment arms but decreased more with ERN treatment. HDL-C and its subfractions increased significantly in both treatment groups, but more so in patients treated with ERN. For the entire study population, neither apoB- nor apoA1-containing lipoprotein subfractions predicted risk at baseline or at 1 year of follow-up. In the high TG and low HDL-C subgroup treated with placebo, changes at 1 year in HDL 2 -C, total cholesterol/HDL 2 -C, and non-HDL-C/HDL 2 -C may be

EFFECT OF THE LEVEL AND TYPE OF DIETARY FAT ON THE METABOLISM OF CHOLESTEROL AND BETA LIPOPROTEINS IN THE CEBUS MONKEY

PubMed Central

Portman, Oscar W.; Hegsted, D. Mark; Stare, Fredrick J.; Bruno, Dorothy; Murphy, Robert; Sinisterra, Leonardo

1956-01-01

A study was carried out to determine the effect of the level and type of dietary fat on the concentration of cholesterol and beta lipoproteins in the sera of Cebus monkeys. Three groups of monkeys were fed isocaloric diets containing a fixed ratio of alpha protein and cholesterol to calories but with different amounts of corn oil and sucrose. Corn oil provided 10, 32, and 45 per cent of the calories in the three diets, and the level of sucrose was varied inversely. After 8 weeks the serum cholesterol and Sf 12 to 100 beta lipoprotein concentrations were significantly greater in the medium and high fat groups. When corn oil was decreased from 45 to 10 per cent of dietary calories and sucrose was increased, the serum cholesterol fell in all cases, and when the reverse change was made, the concentration of serum cholesterol increased. Variation in dietary sucrose had no specific effect. Substitution of starch for sucrose with diets otherwise constant did not cause significant change in the concentration of serum cholesterol. When monkeys fed corn oil diets at any of three levels were changed to hydrogenated cottonseed oil diets at the same level, the serum cholesterol and Sf 12 to 100 beta lipoproteins rose. However, hydrogenated cottonseed oil had no greater hypercholesteremic effect than did corn oil in the absence of dietary cholesterol. Diets containing lard with cholesterol also produced strikingly greater serum lipide responses than did diets based on corn oil and cholesterol. Hydrogenated cottonseed oil had a greater hypercholesteremic effect than an unhydrogenated cottonseed oil from the same lot. Preliminary studies indicated that the saturated fats (hydrogenated cottonseed oil) produced the most striking elevation of serum cholesterol values (above controls fed corn oil) when casein was the dietary protein. PMID:13376806

Mouse, but Not Human, ApoB-100 Lipoprotein Cholesterol Is a Potent Innate Inhibitor of Streptococcus pneumoniae Pneumolysin

PubMed Central

Wade, Kristin R.; Hotze, Eileen M.; Briles, David E.; Tweten, Rodney K.

2014-01-01

Streptococcus pneumoniae produces the pore-forming toxin pneumolysin (PLY), which is a member of the cholesterol-dependent cytolysin (CDC) family of toxins. The CDCs recognize and bind the 3β-hydroxyl group of cholesterol at the cell surface, which initiates membrane pore formation. The cholesterol transport lipoproteins, which carry cholesterol in their outer monolayer, are potential off-pathway binding targets for the CDCs and are present at significant levels in the serum and the interstitial spaces of cells. Herein we show that cholesterol carried specifically by the ApoB-100-containing lipoprotein particles (CH-ApoB-100) in the mouse, but not that carried by human or guinea pig particles, is a potent inhibitor of the PLY pore-forming mechanism. Cholesterol present in the outer monolayer of mouse ApoB-100 particles is recognized and bound by PLY, which stimulates premature assembly of the PLY oligomeric complex thereby inactivating PLY. These studies further suggest that the vast difference in the inhibitory capacity of mouse CH-ApoB-100 and that of the human and the guinea pig is due to differences in the presentation of cholesterol in the outer monolayer of their ApoB-100 particles. Therefore mouse CH-ApoB-100 represents a significant innate CDC inhibitor that is absent in humans, which may underestimate the contribution of CDCs to human disease when utilizing mouse models of disease. PMID:25188225

High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.

PubMed

Gordon, D J; Probstfield, J L; Garrison, R J; Neaton, J D; Castelli, W P; Knoke, J D; Jacobs, D R; Bangdiwala, S; Tyroler, H A

1989-01-01

The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.

Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.

PubMed

Xie, C; Turley, S D; Dietschy, J M

1999-10-12

Niemann-Pick type C (NPC) disease is associated with the accumulation of unesterified cholesterol in nearly all tissues and with progressive neurodegeneration. A murine model of this disease, the NPC mouse, was used to determine whether this sequestered cholesterol represented sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs. This was 7-fold greater than the rate of accumulation in control mice. The rate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and accounted for the uptake of 78 mg/day per kg of cholesterol in LDL whereas 8 mg/day per kg was taken up from CMs. Deletion of the LDL receptor in NPC mice altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL cholesterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterified cholesterol in that organ. Together, these observations strongly support the conclusion that, in NPC disease, it is cholesterol carried in LDL and CMs that is sequestered in the tissues and not sterol that is newly synthesized and carried in high density lipoprotein.

Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries.

PubMed

Sacks, Frank M; Hermans, Michel P; Fioretto, Paola; Valensi, Paul; Davis, Timothy; Horton, Edward; Wanner, Christoph; Al-Rubeaan, Khalid; Aronson, Ronnie; Barzon, Isabella; Bishop, Louise; Bonora, Enzo; Bunnag, Pongamorn; Chuang, Lee-Ming; Deerochanawong, Chaicharn; Goldenberg, Ronald; Harshfield, Benjamin; Hernández, Cristina; Herzlinger-Botein, Susan; Itoh, Hiroshi; Jia, Weiping; Jiang, Yi-Der; Kadowaki, Takashi; Laranjo, Nancy; Leiter, Lawrence; Miwa, Takashi; Odawara, Masato; Ohashi, Ken; Ohno, Atsushi; Pan, Changyu; Pan, Jiemin; Pedro-Botet, Juan; Reiner, Zeljko; Rotella, Carlo Maria; Simo, Rafael; Tanaka, Masami; Tedeschi-Reiner, Eugenia; Twum-Barima, David; Zoppini, Giacomo; Carey, Vincent J

2014-03-04

Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11-1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88-0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16-1.31) with triglycerides and decreased by 0.86 (0.82-0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis

PubMed Central

Chen, Jing; Zhang, Xiaolu; Kusumo, Handojo; Costa, Lucio G.; Guizzetti, Marina

2012-01-01

Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS. PMID:23010475

The triglyceride to high-density lipoprotein-cholesterol ratio in adolescence and subsequent weight gain predict nuclear magnetic resonance-measured lipoprotein subclasses in adulthood.

PubMed

Weiss, Ram; Otvos, James D; Sinnreich, Ronit; Miserez, Andre R; Kark, Jeremy D

2011-01-01

To assess whether the fasting triglyceride-to-high-density lipoprotein (HDL)-cholesterol (TG/HDL) ratio in adolescence is predictive of a proatherogenic lipid profile in adulthood. A longitudinal follow-up of 770 Israeli adolescents 16 to 17 years of age who participated in the Jerusalem Lipid Research Clinic study and were reevaluated 13 years later. Lipoprotein particle size was assessed at the follow-up with proton nuclear magnetic resonance. The TG/HDL ratio measured in adolescence was strongly associated with low-density lipoprotein, very low-density lipoprotein (VLDL), and HDL mean particle size in young adulthood in both sexes, even after adjustment for baseline body mass index and body mass index change. The TG/HDL ratio measured in adolescence and subsequent weight gain independently predicted atherogenic small low-density lipoprotein and large VLDL particle concentrations (P < .001 in both sexes). Baseline TG/HDL and weight gain interacted to increase large VLDL concentration in men (P < .001). Adolescents with an elevated TG/HDL ratio are prone to express a proatherogenic lipid profile in adulthood. This profile is additionally worsened by weight gain. Copyright © 2011 Mosby, Inc. All rights reserved.

Role of dietary supplements in lowering low-density lipoprotein cholesterol: a review.

PubMed

Nijjar, Prabhjot S; Burke, Frances M; Bloesch, Annette; Rader, Daniel J

2010-01-01

Coronary heart disease (CHD) remains a major source of morbidity and mortality. As the epidemic of obesity, diabetes, and hypertension continues to grow among young adults, the population at risk for atherosclerotic CHD is ever increasing. More than a century of laboratory and human findings link cholesterol levels with a propensity to develop atherosclerosis. Low-density lipoprotein (LDL) is the major atherogenic lipoprotein, and numerous clinical trials have shown the efficacy of lowering LDL-cholesterol (LDL-C) for reducing CHD risk. New trial data have resulted in LDL-C goals being lowered over time and expansion of the population of patients that are candidates for LDL-lowering therapy to decrease their lifetime risk of CHD. Although statins are relatively safe and well tolerated, there are still significant numbers of patients who cannot tolerate them and many others who only require mild LDL-C reduction and prefer nonprescription alternatives to statin therapy. A number of dietary supplements and functional foods have been suggested to reduce LDL-C levels, but only a few have withstood the rigors of randomized controlled trials. Here we review the evidence in support of dietary supplements and their LDL-C-lowering effects. We also review supplements that, after initial excitement about their purported effect, were not found to lower LDL-C significantly. Copyright © 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, Triglycerides, and Apolipoprotein B and Cardiovascular Risk in Patients With Manifest Arterial Disease.

PubMed

van den Berg, M Johanneke; van der Graaf, Yolanda; de Borst, Gert Jan; Kappelle, L Jaap; Nathoe, Hendrik M; Visseren, Frank L J

2016-09-15

Low-density lipoprotein cholesterol (LDL-C) only partly represents the atherogenic lipid burden, and a growing body of evidence suggests that non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and apolipoprotein B (apoB) are more accurate in estimating lipid-related cardiovascular disease risk. Our objective was to compare the relation among LDL-C, non-HDL-C, triglycerides, and apoB and the occurrence of future vascular events and mortality in patients with manifest arterial disease. This is a prospective cohort study of 7,216 patients with clinically manifest arterial disease in the Secondary Manifestations of Arterial Disease Study. Cox proportional hazard models were used to quantify the risk of major cardiovascular events (MACE; i.e., stroke, myocardial infarction, and vascular mortality) and all-cause mortality. Interaction was tested for type of vascular disease at inclusion. MACE occurred in 1,185 subjects during a median follow-up of 6.5 years (interquartile range 3.4 to 9.9 years). Adjusted hazard ratios (HRs) of MACE per 1 SD higher were for LDL-C (HR 1.15, 95% confidence interval [CI] 1.09 to 1.22), for non-HDL-C (HR 1.17, 95% CI 1.11 to 1.23), for log(triglycerides) (HR 1.12, 95% CI 1.06 to 1.19), and for apoB HR (1.12, 95% CI 0.99 to 1.28). The relation among LDL-C, non-HDL-C, and cardiovascular events was comparable in patients with cerebrovascular disease, coronary artery disease, or polyvascular disease and absent in those with aneurysm of abdominal aorta or peripheral artery disease. In conclusion, in patients with a history of cerebrovascular, coronary artery, or polyvascular disease, but not aneurysm of abdominal aorta or peripheral artery disease, higher levels of LDL-C and non-HDL-C are related to increased risk of future MACE and of comparable magnitude. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of MAT9001 containing eicosapentaenoic acid and docosapentaenoic acid, compared to eicosapentaenoic acid ethyl esters, on triglycerides, lipoprotein cholesterol, and related variables.

PubMed

Maki, Kevin C; Bobotas, George; Dicklin, Mary R; Huebner, Margie; Keane, William F

Long-chain omega-3 fatty acid concentrate pharmaceuticals are used in the United States for treatment of severe hypertriglyceridemia (≥500 mg/dL) and are under investigation as adjuncts to statins for lowering cardiovascular risk in patients with high triglycerides (TGs; 200-499 mg/dL). To evaluate MAT9001, an investigational prescription-only omega-3 fatty acid agent containing predominantly eicosapentaenoic acid (EPA) and docosapentaenoic acid, in 42 men and women with fasting TG 200 to 400 mg/dL. In this open-label, crossover trial, subjects received MAT9001 and EPA ethyl esters (EPA-EE) in random order. They were housed in a clinical research unit for 2 14-day treatment periods, separated by a ≥35-day washout. Lipoprotein lipids, apolipoproteins (Apos) and proprotein convertase subtilisin kexin type 9 levels were measured before and at the end of each treatment period. MAT9001, compared with EPA-EE, resulted in significantly (P < .05) larger reductions from pretreatment levels for TG (-33.2% vs -10.5%), total cholesterol (-9.0% vs -6.2%), non-high-density lipoprotein cholesterol (-8.8% vs -4.6%), very low-density lipoprotein cholesterol (-32.5% vs -8.1%), Apo C3 (-25.5% vs -5.0%), and proprotein convertase subtilisin kexin type 9 (-12.3% vs +8.8%). MAT9001 also produced a significantly (P = .003) larger reduction in Apo A1 (-15.3% vs -10.2%), but responses for high-density lipoprotein cholesterol (-11.3% vs -11.1%), low-density lipoprotein cholesterol (-2.4% vs -4.3%), and Apo B (-3.8% vs -0.7%), respectively, were not significantly different relative to EPA-EE. MAT9001 produced significantly larger reductions than EPA-EE in several lipoprotein-related variables that would be expected to favorably alter cardiovascular disease risk in men and women with hypertriglyceridemia. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain.

PubMed

Zhang, D-D; Yu, H-L; Ma, W-W; Liu, Q-R; Han, J; Wang, H; Xiao, R

2015-08-06

Cholesterol metabolism is important for neuronal function in the central nervous system (CNS). The oxysterol 27-hydroxycholesterol (27-OHC) is a cholesterol metabolite that crosses the blood-brain barrier (BBB) and may be a useful substitutive marker for neurodegenerative diseases. However, the effects of 27-OHC on learning and memory and the underlying mechanisms are unclear. To determine this mechanism, we investigated learning and memory and cholesterol metabolism in rat brain following the injection of various doses of 27-OHC into the caudal vein. We found that 27-OHC increased cholesterol levels and upregulated the expression of liver X receptor-α (LXR-α) and adenosine triphosphate (ATP)-binding cassette transporter protein family member A1 (ABCA1). In addition, 27-OHC decreased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low-density lipoprotein receptor (LDLR) in rat brain tissues. These findings suggest that 27-OHC may negatively modulate cognitive effects and cholesterol metabolism in the brain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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

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

USDA-ARS?s Scientific Manuscript database

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...

Correlation of structural stability with functional remodeling of high-density lipoproteins: the importance of being disordered.

PubMed

Guha, Madhumita; Gao, Xuan; Jayaraman, Shobini; Gursky, Olga

2008-11-04

High-density lipoproteins (HDLs) are protein-lipid assemblies that remove excess cell cholesterol and prevent atherosclerosis. HDLs are stabilized by kinetic barriers that decelerate protein dissociation and lipoprotein fusion. We propose that similar barriers modulate metabolic remodeling of plasma HDLs; hence, changes in particle composition that destabilize HDLs and accelerate their denaturation may accelerate their metabolic remodeling. To test this notion, we correlate existing reports on HDL-mediated cell cholesterol efflux and esterification, which are obligatory early steps in cholesterol removal, with our kinetic studies of HDL stability. The results support our hypothesis and show that factors accelerating cholesterol efflux and esterification in model discoidal lipoproteins (including reduced protein size, reduced fatty acyl chain length, and/or increased level of cis unsaturation) destabilize lipoproteins and accelerate their fusion and apolipoprotein dissociation. Oxidation studies of plasma spherical HDLs show a similar trend: mild oxidation by Cu(2+) or OCl(-) accelerates cell cholesterol efflux, protein dissociation, and HDL fusion, while extensive oxidation inhibits these reactions. Consequently, moderate destabilization may be beneficial for HDL functions by facilitating insertion of cholesterol and lipophilic enzymes, promoting dissociation of lipid-poor apolipoproteins, which are primary acceptors of cell cholesterol, and thereby accelerating HDL metabolism. Therefore, HDL stability must be delicately balanced to maintain the structural integrity of the lipoprotein assembly and ensure structural specificity necessary for interactions of HDL with its metabolic partners, while facilitating rapid HDL remodeling and turnover at key junctures of cholesterol transport. The inverse correlation between HDL stability and remodeling illustrates the functional importance of structural disorder in macromolecular assemblies stabilized by kinetic barriers.

[The real measurement of non-HDL-cholesterol: Atherogenic cholesterol].

PubMed

Millán, Jesús; Hernández-Mijares, Antonio; Ascaso, Juan F; Blasco, Mariano; Brea, Angel; Díaz, Ángel; González-Santos, Pedro; Mantilla, Teresa; Pedro-Botet, Juan; Pintó, Xavier

Lowe density lipoproteins (LDL) are the causal agent of cardiovascular diseases. In practice, we identify LDL with cholesterol transported in LDL (cLDL). So, cLDL has become the major target for cardiovascular prevention. Howewer, we have progressive evidences about the role of triglycerides rich lipoproteins, particularly those very low density lipoprotein (VLDL) in promotion and progression of atherosclerosis, that leads cholesterol in VLDL and its remanents as a potential therapeutic target. This feature is particularly important and of a great magnitude, in patients with hypertiglyceridemia. We can to considere, that the non-HDL cholesterol -cLDL+cVLDL+c-remmants+Lp(a)- is the real measurement of atherogenic cholesterol. In addition, non-HDL-cholesterol do not show any variations between postprandial states. In fact, non-HDL-cholesterol should be an excellent marker of atherogenic cholesterol, and an major therapeutic target in patients with atherogenic dyslipidaemia. According with different clinical trials and with the epidemiological and mendelian studies, in patients with high cardiovascular risk, optimal level of cLDL will be under 70mg/dl, and under 100 ng/dl for non-HDL-cholesterol; and in high risk patients, 100mg/dl and 130mg/dl, respectively. Copyright © 2016. Publicado por Elsevier España, S.L.U.

FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver.

PubMed

Papazyan, Romeo; Liu, Xueqing; Liu, Jingwen; Dong, Bin; Plummer, Emily M; Lewis, Ronald D; Roth, Jonathan D; Young, Mark A

2018-06-01

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

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.

Secular trends in cholesterol lipoproteins and triglycerides and prevalence of dyslipidemias in an urban Indian population

PubMed Central

Gupta, Rajeev; Guptha, Soneil; Agrawal, Aachu; Kaul, Vijay; Gaur, Kiran; Gupta, Vijay P

2008-01-01

Background Coronary heart disease is increasing in urban Indian subjects and lipid abnormalities are important risk factors. To determine secular trends in prevalence of various lipid abnormalities we performed studies in an urban Indian population. Methods Successive epidemiological Jaipur Heart Watch (JHW) studies were performed in Western India in urban locations. The studies evaluated adults ≥ 20 years for multiple coronary risk factors using standardized methodology (JHW-1, 1993–94, n = 2212; JHW-2, 1999–2001, n = 1123; JHW-3, 2002–03, n = 458, and JHW-4 2004–2005, n = 1127). For the present analyses data of subjects 20–59 years (n = 4136, men 2341, women 1795) have been included. In successive studies, fasting measurements for cholesterol lipoproteins (total cholesterol, LDL cholesterol, HDL cholesterol) and triglycerides were performed in 193, 454, 179 and 252 men (n = 1078) and 83, 472, 195, 248 women (n = 998) respectively (total 2076). Age-group specific levels of various cholesterol lipoproteins, triglycerides and their ratios were determined. Prevalence of various dyslipidemias (total cholesterol ≥ 200 mg/dl, LDL cholesterol ≥ 130 mg/dl, non-HDL cholesterol ≥ 160 mg/dl, triglycerides ≥ 150 mg/dl, low HDL cholesterol <40 mg/dl, high cholesterol remnants ≥ 25 mg/dl, and high total:HDL cholesterol ratio ≥ 5.0, and ≥ 4.0 were also determined. Significance of secular trends in prevalence of dyslipidemias was determined using linear-curve estimation regression. Association of changing trends in prevalence of dyslipidemias with trends in educational status, obesity and truncal obesity (high waist:hip ratio) were determined using two-line regression analysis. Results Mean levels of various lipoproteins increased sharply from JHW-1 to JHW-2 and then gradually in JHW-3 and JHW-4. Age-adjusted mean values (mg/dl) in JHW-1, JHW-2, JHW-3 and JHW-4 studies respectively showed a significant increase in total cholesterol (174.9 ± 45, 196.0 �

Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II.

PubMed

Nicolas, Xavier; Djebli, Nassim; Rauch, Clémence; Brunet, Aurélie; Hurbin, Fabrice; Martinez, Jean-Marie; Fabre, David

2018-05-03

Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. This model successfully allowed the

Metabolism of cholesteryl esters of rat very low density lipoproteins.

PubMed

Faergeman, O; Havel, R J

1975-06-01

Rat very low density lipoproteins (d smaller than 1.006), biologically labeled in esterified and free cholesterol, were obtained form serum 6 h after intravenous injection of particulate (3-H) cholesterol. When injected into recipient animals, the esterified cholesterol was cleared form plasma with a half-life of 5 min. After 15 min, 71% of the injected esterified (3-H) cholesterol had been taken up by the liver, where it was rapidly hydrolyzed. After 60 min only 3.3% of the amount injected had been transferred, via lipoproteins of intermediate density, to the low density lipoproteins of plasma (d 1.019-1.063). Both uptake in the liver and transfer to low density lipoproteins occurred without change of distribution of 3-H in the various cholesteryl esters. 3-H appearing in esterified cholesterol of high density lipoproteins (d greater than 1.063) was derived from esterification, presumably by lecithin: cholesterol acyltransferase, of simultaneously injected free (3-H) cholesterol. Content of free (3-H) cholesterol in the very low density lipoproteins used for injection could be reduced substantially by incubation with erythrocytes. This procedure, however, increased the rate of clearance of the lipoproteins after injection into recipient rats. These studies show that hepatic removal is the major catabolic pathway for cholesteryl esters of rat very low density lipoproteins and that transfer to low density lipoproteins occurs to only a minor extent.

Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect.

PubMed

Cairoli, E; Rebella, M; Danese, N; Garra, V; Borba, E F

2012-10-01

The influence of antimalarials on lipids in systemic lupus erythematosus (SLE) has been identified in several studies but not in many prospective cohorts. The aim of this study was to longitudinally determine the effect of antimalarials on the lipoprotein profile in SLE. Fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol (LDL) plasma levels were determined at entry and after 3 months of hydroxychloroquine (HCQ) treatment in a longitudinal evaluation of 24 patients with SLE. a significant decrease in TC (198 ± 33.7 vs. 183 ± 30.3 mg/dl, p = 0.023) and LDL levels (117 ± 31.3 vs. 101 ± 26.2 mg/dl, p = 0.023) were detected after the 3 months of HCQ therapy. The reduction of 7.6% in TC (p = 0.055) and 13.7% in LDL levels (p = 0.036) determined a significant decrease in the frequency of dyslipidemia (26% vs. 12.5%, p = 0.013) after HCQ therapy. This longitudinal study demonstrated the beneficial effect of antimalarials on lipids in SLE since this therapy induced a reduction of atherogenic lipoproteins.

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

PubMed Central

Chapman, M. John; Ginsberg, Henry N.; Amarenco, Pierre; Andreotti, Felicita; Borén, Jan; Catapano, Alberico L.; Descamps, Olivier S.; Fisher, Edward; Kovanen, Petri T.; Kuivenhoven, Jan Albert; Lesnik, Philippe; Masana, Luis; Nordestgaard, Børge G.; Ray, Kausik K.; Reiner, Zeljko; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Tybjærg-Hansen, Anne; Watts, Gerald F.

2011-01-01

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. PMID:21531743

Nanostructured NiO-based reagentless biosensor for total cholesterol and low density lipoprotein detection.

PubMed

Kaur, Gurpreet; Tomar, Monika; Gupta, Vinay

2017-03-01

Nanostructured nickel oxide (NiO) thin film has been explored as a matrix to develop a reagentless biosensor for free and total cholesterol as well as low density lipoprotein (LDL) detection. The redox property of the matrix has been exploited to enhance the electron transfer between the enzyme and the electrode as well as to eliminate the toxic mediator in solution. X-ray diffraction, scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy were carried out to characterize the NiO thin film. Biosensing response studies were accomplished using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). The developed biosensors exhibited a high sensitivity of 27 and 63 μA/mM/cm 2 over a linear range of 0.12-10.23 and 1-12 mM, respectively, for free and total cholesterol. Reagentless estimation of LDL was also achieved over the wide range 0.018-0.5 μM with a sensitivity of 0.12 mA/μM/cm 2 . The results are extremely promising for the realization of an integrated biosensor for complete detection of cholesterol in the serum samples. Graphical Abstract Reagentless sensing mechanism of (a) free cholesterol and (b) total cholesterol using nanostructured NiO matrix.

Background diet and fat type alters plasma lipoprotein response but not aortic cholesterol accumulation in F1B Golden Syrian hamsters.

PubMed

Dillard, Alice; Matthan, Nirupa R; Spartano, Nicole L; Butkowski, Ann E; Lichtenstein, Alice H

2013-12-01

Dietary modification alters plasma lipoprotein profiles and atherosclerotic lesion progression in humans and some animal models. Variability in response to diet induced atherosclerosis has been reported in hamsters. Assessed was the interaction between background diet composition and dietary fat type on aortic cholesterol accumulation, lipoprotein profiles, hepatic lipids and selected genes. F1B Golden Syrian hamsters (20/group) were fed (12 weeks) semi-purified or non-purified diets containing either 10 % (w/w) coconut oil or safflower oil and 0.15 % (w/w) cholesterol. The non-purified diets relative to semi-purified diets resulted in significantly higher TC (72 % [percent difference] and 38 %, coconut oil and safflower oil, respectively) and nHDL-C (84 and 61 %, coconut oil and safflower oil, respectively), and lower HDL-C (-47 and -45 %, coconut oil and safflower oil, respectively) concentrations. Plasma triacylglycerol concentrations in the hamsters fed the non-purified coconut oil-supplemented diets were three- to fourfold higher than non-purified safflower oil-supplemented, and both semi-purified diets. With the exception of HDL-C, a significant effect of fat type was observed in TC, nHDL-C and triacylglycerol (all P < 0.05) concentrations. Regardless of diet induced differences in lipoprotein profiles, there was no significant effect on aortic cholesterol accumulation. There was an inverse relationship between plasma nHDL-C and triacylglycerol, and hepatic cholesteryl ester content (P < 0.001). Diet induced differences in hepatic gene transcription (LDL receptor, apoB-100, microsomal transfer protein) were not reflected in protein concentrations. Although hamsters fed non-purified and/or saturated fatty acid-supplemented diets had more atherogenic lipoprotein profiles compared to hamsters fed semi-purified and/or polyunsaturated fatty acid-supplemented diets these differences were not reflected in aortic cholesterol accumulation.

Oxidation of cholesterol moiety of low density lipoprotein in the presence of human endothelial cells or Cu+2 ions: identification of major products and their effects.

PubMed

Bhadra, S; Arshad, M A; Rymaszewski, Z; Norman, E; Wherley, R; Subbiah, M T

1991-04-15

Oxidation of lipoproteins is believed to play a key role in atherogenesis. In this study, low density lipoproteins (LDL) was subjected to oxidation in the presence of either human umbilical vein endothelial cells or with Cu+2 ions and the major oxides formed were identified. While cholesterol-alpha-epoxide (C-alpha EP) was the major product of cholesterol peroxidation in the presence of endothelial cells, cholest-3,5-dien-7-one (CD) predominated in the presence of Cu+2 ion. Both steroids were identified by gas chromatography/mass spectrometry. HDL cholesterol was resistant to oxidation. When tested on human skin fibroblasts in culture C-alpha EP (10 micrograms/ml) caused marked stimulation of 14C-oleate incorporation into cholesterol esters, while CD stimulated cholesterol esterification only mildly. These studies show that a) C-alpha EP is the major peroxidation product of LDL cholesterol moiety in the presence of endothelial cells and b) it causes marked stimulation of cholesterol esterification in cells. C-alpha EP may play a key role in increasing cholesterol esterification noted in atherogenesis.

Membrane Cholesterol Modulates Superwarfarin Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marangoni, M. Natalia; Martynowycz, Michael W.; Kuzmenko, Ivan

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 notmore » 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.« less

Is High-Density Lipoprotein Cholesterol Causally Related to Kidney Function? Evidence From Genetic Epidemiological Studies.

PubMed

Coassin, Stefan; Friedel, Salome; Köttgen, Anna; Lamina, Claudia; Kronenberg, Florian

2016-11-01

A recent observational study with almost 2 million men reported an association between low high-density lipoprotein (HDL) cholesterol and worse kidney function. The causality of this association would be strongly supported if genetic variants associated with HDL cholesterol were also associated with kidney function. We used 68 genetic variants (single-nucleotide polymorphisms [SNPs]) associated with HDL cholesterol in genome-wide association studies including >188 000 subjects and tested their association with estimated glomerular filtration rate (eGFR) using summary statistics from another genome-wide association studies meta-analysis of kidney function including ≤133 413 subjects. Fourteen of the 68 SNPs (21%) had a P value <0.05 compared with the 5% expected by chance (Binomial test P=5.8×10 - 6 ). After Bonferroni correction, 6 SNPs were still significantly associated with eGFR. The genetic variants with the strongest associations with HDL cholesterol concentrations were not the same as those with the strongest association with kidney function and vice versa. An evaluation of pleiotropy indicated that the effects of the HDL-associated SNPs on eGFR were not mediated by HDL cholesterol. In addition, we performed a Mendelian randomization analysis. This analysis revealed a positive but nonsignificant causal effect of HDL cholesterol-increasing variants on eGFR. In summary, our findings indicate that HDL cholesterol does not causally influence eGFR and propose pleiotropic effects on eGFR for some HDL cholesterol-associated SNPs. This may cause the observed association by mechanisms other than the mere HDL cholesterol concentration. © 2016 The Authors.

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

PubMed

Smith, Caren E; Arnett, Donna K; Tsai, Michael Y; Lai, Chao-Qiang; Parnell, Laurence D; Shen, Jian; Laclaustra, Martin; Junyent, Mireia; Ordovás, José M

2009-10-01

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 polymorphisms in the key regulators of HDL metabolism including endothelial lipase (LIPG). We examined associations between variants LIPG T111I (rs2000813) and LIPG i24582 (rs6507931), HDL and television viewing/computer use ("screen time") as a marker for physical inactivity in a population with high prevalence of metabolic syndrome. Subjects consisted of 539 White men and 584 women (mean+/-S.D., 49+/-16 years) participating in the GOLDN study. We did not observe an association with either LIPG SNP or HDL independently of screen time. In multi-adjusted linear regression models, HDL interacted significantly with screen time as a continuous variable in LIPG i24582 subjects with TT genotype (P<0.05). By dichotomizing screen time into high and low levels, we found significant genotype-associated differences in HDL in women but not men. When screen time was >or=2.6h/day, the concentrations of total HDL-C, large HDL, large low density lipoprotein (LDL) were lower, the concentration of small LDL was higher and HDL and LDL particle sizes were smaller in subjects with LIPG i24582 TT compared to CT and CC subjects (P<0.05). We found a significant gene-physical inactivity interaction for HDL and some LDL measures for the LIPG i24582 polymorphism. Higher levels of physical activity may be protective for HDL-C concentrations and low activity detrimental in LIPG i24582 TT individuals, especially in women.

SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet.

PubMed

Potì, Francesco; Ceglarek, Uta; Burkhardt, Ralph; Simoni, Manuela; Nofer, Jerzy-Roch

2015-05-01

Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-α and endothelial adhesion molecules (sICAM-1, sVCAM-1). Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The role of high-density lipoprotein cholesterol in risk for posttraumatic stress disorder: taking a nutritional approach toward universal prevention.

PubMed

Hamazaki, K; Nishi, D; Yonemoto, N; Noguchi, H; Kim, Y; Matsuoka, Y

2014-09-01

Several cross-sectional studies, but no prospective studies, have reported an association between an abnormal lipid profile and posttraumatic stress disorder (PTSD). We hypothesized that an abnormal lipid profile might predict risk for developing PTSD. In this prospective study, we analyzed data from 237 antidepressant-naïve severely injured patients who participated in the Tachikawa Cohort of Motor Vehicle Accident Study. High-density lipoprotein cholesterol (HDL-C) levels at baseline were significantly lower in patients with PTSD than those without PTSD at 6 months after motor vehicle accident (MVA) and were inversely associated with risk for PTSD. In contrast, triglycerides (TG) at baseline were significantly higher in patients with PTSD than in those without PTSD at 6 months post-MVA and were positively associated with risk for PTSD. There was no clear association between low-density lipoprotein cholesterol or total cholesterol and risk for PTSD. In conclusion, low HDL-C and high TG may be risk factors for PTSD. Determining lipid profiles might help identify those at risk for PTSD after experiencing trauma. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Streptococcal Serum Opacity Factor Increases Hepatocyte Uptake of Human Plasma High Density Lipoprotein-Cholesterol1

PubMed Central

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

2010-01-01

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 ~400,000 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. [3H]CE uptake by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was respectively 2.4 and 4.5 times faster than from control HDL. CERM-[3H]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-[3H]CE uptake by both receptors. RAP and heparin inhibit CERM-[3H]CE but not HDL-[3H]CE uptake thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789

Status of non-HDL-cholesterol and LDL-cholesterol among subjects with and without metabolic syndrome.

PubMed

Khan, Sikandar Hayat; Asif, Naveed; Ijaz, Aamir; Manzoor, Syed Mohsin; Niazi, Najumusaquib Khan; Fazal, Nadeem

2018-04-01

To to compare non-high-density lipoprotein and low-density lipoprotein cholesterol among subjects with or without metabolic syndrome, glycation status and nephropathic changes. The comparative cross-sectional study was carried out from Dec 21, 2015, to Nov 15, 2016, at the department of pathology and medicine PNS HAFEEZ and department of chemical pathology and clinical endocrinology (AFIP), and comprised patients of either gender visiting the out-patient department for routine screening. They were evaluated for anthropometric indices, blood pressure and sampled for lipid profile, fasting plasma glucose, glycated haemoglobin, insulin, and urine albumin-to-creatinine ratio. Subjects were segregated based upon presence (Group1) or absence (Group2) of metabolic syndrome based upon criteria of National Cholesterol Education Programme and the International Diabetes Federation. Differences in high and low density lipoprotein cholesterols were calculated between the groups. Of the 229 subjects, 120(52.4%) were women and 109(47.6%) were men. Overall, there were 107(46.7%) subjects in Group 1, and 122(53.3%) in Group 2. Non-high-density lipoprotein cholesterol was significantly different between subjects with and without metabolic syndrome as per both the study criteria (p<0.05 each). . Non-high-density lipoprotein cholesterol levels were higher in subjects with metabolic syndrome.

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

PubMed Central

Smith, Caren E.; Arnett, Donna K.; Tsai, Michael Y.; Lai, Chao-Qiang; Parnell, Laurence D.; Shen, Jian; Laclaustra, Martin; Junyent, Mireia; Ordovás, José M.

2009-01-01

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 polymorphisms in the key regulators of HDL metabolism including endothelial lipase (LIPG). Methods We examined associations between variants LIPG T111I (rs2000813) and LIPG i24582 (rs6507931), HDL and television viewing/computer use (“screen time”) as a marker for physical inactivity in a population with high prevalence of metabolic syndrome. Subjects consisted of 539 White men and 584 women (mean ± S.D., 49 ± 16 years) participating in the GOLDN study. Results We did not observe an association with either LIPG SNP or HDL independently of screen time. In multi-adjusted linear regression models, HDL interacted significantly with screen time as a continuous variable in LIPG i24582 subjects with TT genotype (P < 0.05). By dichotomizing screen time into high and low levels, we found significant genotype-associated differences in HDL in women but not men. When screen time was ≥2.6 h/day, the concentrations of total HDL-C, large HDL, large low density lipoprotein (LDL) were lower, the concentration of small LDL was higher and HDL and LDL particle sizes were smaller in subjects with LIPG i24582 TT compared to CT and CC subjects (P < 0.05). Conclusions We found a significant gene-physical inactivity interaction for HDL and some LDL measures for the LIPG i24582 polymorphism. Higher levels of physical activity may be protective for HDL-C concentrations and low activity detrimental in LIPG i24582 TT individuals, especially in women. PMID:19380136

Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.

PubMed Central

Clarke, R.; Frost, C.; Collins, R.; Appleby, P.; Peto, R.

1997-01-01

OBJECTIVE: To determine the quantitative importance of dietary fatty acids and dietary cholesterol to blood concentrations of total, low density lipoprotein, and high density lipoprotein cholesterol. DESIGN: Meta-analysis of metabolic ward studies of solid food diets in healthy volunteers. SUBJECTS: 395 dietary experiments (median duration 1 month) among 129 groups of individuals. RESULTS: Isocaloric replacement of saturated fats by complex carbohydrates for 10% of dietary calories resulted in blood total cholesterol falling by 0.52 (SE 0.03) mmol/l and low density lipoprotein cholesterol falling by 0.36 (0.05) mmol/l. Isocaloric replacement of complex carbohydrates by polyunsaturated fats for 5% of dietary calories resulted in total cholesterol falling by a further 0.13 (0.02) mmol/l and low density lipoprotein cholesterol falling by 0.11 (0.02) mmol/l. Similar replacement of carbohydrates by monounsaturated fats produced no significant effect on total or low density lipoprotein cholesterol. Avoiding 200 mg/day dietary cholesterol further decreased blood total cholesterol by 0.13 (0.02) mmol/l and low density lipoprotein cholesterol by 0.10 (0.02) mmol/l. CONCLUSIONS: In typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol. PMID:9006469

Examination of the relation between periodontal health status and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen.

PubMed

Wu, T; Trevisan, M; Genco, R J; Falkner, K L; Dorn, J P; Sempos, C T

2000-02-01

Using data from the Third National Health and Nutrition Examination Survey (1988-1994), the authors examined the relation between periodontal health and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. A total of 10,146 participants were included in the analyses of cholesterol and C-reactive protein and 4,461 in the analyses of fibrinogen. Periodontal health indicators included the gingival bleeding index, calculus index, and periodontal disease status (defined by pocket depth and attachment loss). While cholesterol and fibrinogen were analyzed as continuous variables, C-reactive protein was dichotomized into two levels. The results show a significant relation between indicators of poor periodontal status and increased C-reactive protein and fibrinogen. The association between periodontal status and total cholesterol level is much weaker. No consistent association between periodontal status and high density lipoprotein cholesterol was detectable. Similar patterns of association were observed for participants aged 17-54 years and those 55 years and older. In conclusion, this study suggests that total cholesterol, C-reactive protein, and fibrinogen are possible intermediate factors that may link periodontal disease to elevated cardiovascular risk.

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)

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. Copyright © 2016. Published by Elsevier Inc.

Controlling for high-density lipoprotein cholesterol does not affect the magnitude of the relationship between alcohol and coronary heart disease.

PubMed

Magnus, Per; Bakke, Eirin; Hoff, Dominic A; Høiseth, Gudrun; Graff-Iversen, Sidsel; Knudsen, Gun Peggy; Myhre, Ronny; Normann, Per Trygve; Næss, Øyvind; Tambs, Kristian; Thelle, Dag S; Mørland, Jørg

2011-11-22

This study tested the hypothesis that moderate alcohol intake exerts its cardioprotective effect mainly through an increase in the serum level of high-density lipoprotein cholesterol. In the Cohort of Norway (CONOR) study, 149 729 adult participants, recruited from 1994 to 2003, were followed by linkage to the Cause of Death Registry until 2006. At recruitment, questionnaire data on alcohol intake were collected, and the concentration of high-density lipoprotein cholesterol in serum was measured. Using Cox regression, we found that the adjusted hazard ratio for men for dying from coronary heart disease was 0.52 (95% confidence interval, 0.39-0.69) when consuming alcohol more than once a week compared with never or rarely. The ratio changed only slightly, to 0.55 (0.41-0.73), after the regression model included the serum level of high-density cholesterol. For women, the corresponding hazard ratios were 0.62 (0.32-1.23) and 0.68 (0.34-1.34), respectively. Alcohol intake is related to a reduced risk of death from coronary heart disease in the follow-up of a large, population-based Norwegian cohort study with extensive control for confounding factors. Our findings suggest that the serum level of high-density cholesterol is not an important intermediate variable in the possible causal pathway between moderate alcohol intake and coronary heart disease.

Association between traditional cholesterol parameters, lipoprotein particle concentration, novel biomarkers and carotid plaques in retired National Football League players.

PubMed

Virani, Salim S; Pompeii, Lisa; Lincoln, Andrew E; Dunn, Reginald E; Tucker, Andrew M; Nambi, Vijay; Nasir, Khurram; Vogel, Robert A; Boone, Jeffrey L; Roberts, Arthur J; Ballantyne, Christie M

2012-06-01

We assessed whether low-density lipoprotein particle concentration (LDL-P) and high-sensitivity C-reactive protein [hs-CRP] can identify subclinical atherosclerosis better than traditional cholesterol parameters in retired National Football League (NFL) players. It is not known whether LDL-P and the biomarker hs-CRP can identify subclinical atherosclerosis better than low-density lipoprotein cholesterol (LDL-C) or non-high-density-lipoprotein cholesterol (non-HDL-C) in retired NFL players, given high prevalence of metabolic syndrome in these players. Carotid artery plaque screening was performed with traditional lipids, LDL-P, and hs-CRP in 996 retired players. Logistic regression analyses comparing highest with the lowest quartile were performed. Carotid artery plaques were seen in 41%. LDL-C (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.06-2.59), non-HDL-C (OR 1.67, 95% CI 1.04-2.67), and LDL-P (OR 2.21, 95% CI 1.35-3.62) were associated with plaques in adjusted models. Among 187 retired players with metabolic syndrome, LDL-C (OR 1.40, 95% CI 0.53-3.72) was not associated with carotid plaques, whereas LDL-P (OR 3.71, 95% CI 1.16-11.84) and non-HDL-C (OR 2.63, 95% CI 0.91-7.63, p=0.07; borderline significant) were associated with carotid plaques. hs-CRP (OR 1.13, 95% CI 0.71-1.79) was not associated with carotid plaques. Carotid artery plaques were common in retired NFL players and were strongly associated with LDL-P, especially among those with metabolic syndrome. hs-CRP was not associated with carotid plaques in this cohort. Published by Elsevier Ireland Ltd.

The effect of preoperative serum triglycerides and high-density lipoprotein-cholesterol levels on the prognosis of breast cancer.

PubMed

Li, Xing; Tang, Hailin; Wang, Jin; Xie, Xinhua; Liu, Peng; Kong, Yanan; Ye, Feng; Shuang, Zeyu; Xie, Zeming; Xie, Xiaoming

2017-04-01

Although dyslipidemia has been documented to be associated with several types of cancer including breast cancer, it remains uncertainty the prognostic value of serum lipid in breast cancer. The purpose of this study is to evaluate the association between the preoperative plasma lipid profile and the prognostic of breast cancer patients. The levels of preoperative serum lipid profile (including cholesterol [CHO], Triglycerides [TG], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], apolipoprotein A-I [ApoAI], and apolipoprotein B [ApoB]) and the clinical data were retrospectively collected and reviewed in 1044 breast cancer patients undergoing operation. Kaplan-Meier method and the Cox proportional hazards regression model were used in analyzing the overall survival [OS] and disease-free survival [DFS]. Combining the receiver-operating characteristic and Kaplan-Meier analysis, we found that preoperative lower TG and HDL-C level were risk factors of breast cancer patients. In multivariate analyses, a decreased HDL-C level showed significant association with worse OS (HR: 0.528; 95% CI: 0.302-0.923; P = 0.025), whereas a decreased TG level showed significant association with worse DFS (HR: 0.569; 95% CI: 0.370-0.873; P = 0.010). Preoperative serum levels of TG and HDL-C may be independent factor to predict outcome in breast cancer patient. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.

PubMed

Akdim, Fatima; Visser, Maartje E; Tribble, Diane L; Baker, Brenda F; Stroes, Erik S G; Yu, Rosie; Flaim, Joann D; Su, John; Stein, Evan A; Kastelein, John J P

2010-05-15

A randomized, double-blind, placebo-controlled, dose-escalation study was conducted to examine the efficacy and safety of mipomersen (ISIS 301012), an antisense inhibitor of apolipoprotein B, when added to conventional lipid-lowering therapy for patients with heterozygous familial hypercholesterolemia. A total of 44 patients were enrolled and were separated into 4 cohorts, with doses ranging from 50 to 300 mg (4:1 active treatment/placebo ratio). Patients received 8 doses subcutaneously during a 6-week treatment period. Patients assigned to the 300-mg dose continued for an additional 7 weeks with once-per-week dosing. The primary efficacy end point was the percentage of change from baseline to week 7 in low-density lipoprotein (LDL) cholesterol. Safety was assessed using the laboratory test results and according to the incidence, severity, and relation of adverse events to drug dose. Mipomersen produced significant reductions in LDL cholesterol and other atherogenic apolipoprotein B-containing lipoproteins. After 6 weeks of treatment, the LDL cholesterol level was reduced by 21% from baseline in the 200-mg/week dose group (p <0.05) and 34% from baseline in the 300-mg/week dose group (p <0.01), with a concomitant reduction in apolipoprotein B of 23% (p <0.05) and 33% (p <0.01), respectively. Injection site reactions were the most common adverse event. Elevations in liver transaminase levels (> or =3 times the upper limit of normal) occurred in 4 (11%) of 36 patients assigned to active treatment; 3 of these patients were in the highest dose group. In conclusion, mipomersen has an incremental LDL cholesterol lowering effect when added to conventional lipid-lowering therapy. Copyright 2010 Elsevier Inc. All rights reserved.

Titration of Serum Lipoproteins with Lipoprotein Precipitants.

DTIC Science & Technology

1981-12-01

Lipid Res 11:583 (1970). 6. Grove, T. H. Effect of reagent pH on determination of high-density lipo- protein cholesterol by precipitation with sodium ...of choles- terol in the supernate plateaued at 43 mg/dl after the beta and prebeta lipo- proteins had been precipitated . The intensities of the two...AD-A113 370 SCHOOL OF AEROSPACE MEDICINE BROOKS AFS TX F/S 6/1 TITRATION OF SERU’LIPOPROTEINS WITH LIPOPROTEIN PRECIPITANTS .(Ul DEC 81 0 A CLARK. J A

Triglyceride to high-density lipoprotein cholesterol ratio predicts worse outcomes after acute ischaemic stroke.

PubMed

Deng, Q-W; Wang, H; Sun, C-Z; Xing, F-L; Zhang, H-Q; Zuo, L; Gu, Z-T; Yan, F-L

2017-02-01

The effect of the triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) on clinical outcomes of acute ischaemic stroke (AIS) patients is unclear. This study sought to determine whether the TG/HDL-C ratio in AIS patients is associated with worse outcomes at 3 months. Acute ischaemic stroke patients who were admitted from 2011 to 2014 were enrolled in this study. TG, total cholesterol (TC), HDL-C and low-density lipoprotein cholesterol (LDL-C) were collected on admission. Three end-points were defined according to the modified Rankin scale (mRS) score at 3 months after symptom onset (excellent outcome, mRS 0-1; good outcome, mRS 0-2; and death, mRS 6). In all, 1006 patients were included (median age 68.5 years; 58.2% male). Higher TG, non-HDL-C and TG/HDL-C were strongly associated with the three end-points after adjustments: excellent [odds ratio (OR) = 1.39, OR 1.89 and OR 2.34, respectively] and good (OR 1.48, OR 2.90 and OR 4.12) outcomes, and death (OR 0.59, OR 0.29 and OR 0.26). According to receiver operating characteristic (ROC) analysis, the best discriminating factor was a TG/HDL-C ≥ 0.87 for excellent outcomes [area under the ROC curve (AUC) 0.596; sensitivity 73.3%; specificity 42.7%] and non-death (AUC 0.674; sensitivity 67.8%; specificity 60.6%) as well as a TG/HDL-C ≥ 1.01 for a good outcome (AUC 0.652; sensitivity 61.6%; specificity 63.2%). Patients with a TG/HDL-C < 0.87 had a 2.94-fold increased risk of death (95% confidence interval 1.89-4.55) compared with patients with a TG/HDL-C ≥ 0.87. A lower TG/HDL-C was independently associated with death and worse outcome at 3 months in AIS. © 2016 EAN.

Diet × genotype interactions in hepatic cholesterol and lipoprotein metabolism in Atlantic salmon (Salmo salar) in response to replacement of dietary fish oil with vegetable oil.

PubMed

Morais, Sofia; Pratoomyot, Jarunan; Torstensen, Bente E; Taggart, John B; Guy, Derrick R; Bell, J Gordon; Tocher, Douglas R

2011-11-01

The present study investigates the effects of genotype on responses to alternative feeds in Atlantic salmon. Microarray analysis of the liver transcriptome of two family groups, lean or fat, fed a diet containing either a fish oil (FO) or a vegetable oil (VO) blend indicated that pathways of cholesterol and lipoprotein metabolism might be differentially affected by the diet depending on the genetic background of the fish, and this was further investigated by real-time quantitative PCR, plasma and lipoprotein biochemical analysis. Results indicate a reduction in VLDL and LDL levels, with no changes in HDL, when FO is replaced by VO in the lean family group, whereas in fat fish fed FO, levels of apoB-containing lipoproteins were low and comparable with those fed VO in both family groups. Significantly lower levels of plasma TAG and LDL-TAG were measured in the fat group that was independent of diet, whereas plasma cholesterol was significantly higher in fish fed the FO diet in both groups. Hepatic expression of genes involved in cholesterol homeostasis, β-oxidation and lipoprotein metabolism showed relatively subtle changes. A significantly lower expression of genes considered anti-atherogenic in mammals (ATP-binding cassette transporter A1, apoAI, scavenger receptor class B type 1, lipoprotein lipase (LPL)b (TC67836) and LPLc (TC84899)) was found in lean fish, compared with fat fish, when fed VO. Furthermore, the lean family group appeared to show a greater response to diet composition in the cholesterol biosynthesis pathway, mediated by sterol-responsive element-binding protein 2. Finally, the presence of three different transcripts for LPL, with differential patterns of nutritional regulation, was demonstrated.

Activation of lipoprotein lipase by lipoprotein fractions of human serum.

PubMed

Bier, D M; Havel, R J

1970-11-01

Triglycerides in fat emulsions are hydrolyzed by lipoprotein lipase only when they are "activated" by serum lipoproteins. The contribution of different lipoprotein fractions to hydrolysis of triglycerides in soybean oil emulsion was assessed by determining the quantity of lipoprotein fraction required to give half-maximal hydrolysis. Most of the activator property of whole serum from normolipidemic, postabsorptive subjects was in high density lipoproteins. Low density lipoproteins and serum from which all lipoprotein classes were removed had little or no activity. Also, little activator was present in guinea pig serum or in very low density poor serum from an individual with lecithin:cholesterol acyltransferase deficiency, both of which are deficient in high density lipoproteins. Human very low density lipoproteins are potent activators and are much more active than predicted from their content of high density lipoprotein-protein. Per unit weight of protein, very low density lipoproteins had 13 times the activity of high density lipoproteins. These observations suggest that one or more of the major apoproteins of very low density lipoproteins, present as a minor constituent of high density lipoproteins, may be required for the activation process.

Lipid and lipoprotein testing in resource-limited laboratories.

PubMed

Myers, Gary L

2003-01-01

The role of total cholesterol (TC) and lipoproteins in the assessment of coronary heart disease (CHD) is firmly established from population and intervention studies. Total and low-density lipoprotein cholesterol (LDLC) levels are positively associated with CHD, and high-density lipoprotein cholesterol (HDLC) levels are negatively associated with CHD. Efforts to identify and treat people at increased risk based on cholesterol and lipoprotein levels have led to more lipid testing and the need for very reliable test results. Thus, quality laboratory services are an essential component of healthcare delivery and play a vital role in any strategy to reduce morbidity and mortality from CHD. In laboratories with limited resources, establishing laboratory capability to measure CHD risk markers may be a considerable challenge. Laboratories face problems in selecting proper techniques, difficulties in equipment availability and maintenance, and shortage of supplies, staffing, and supervision. The Centers for Disease Control and Prevention (CDC) has been providing technical assistance for more than 30 years to laboratories that measure lipids and lipoproteins and is willing to provide technical assistance as needed for other laboratories to develop this capability. CDC can provide technical assistance to establish lipid and lipoprotein testing capability to support a CHD public health program in areas with limited laboratory resources. This assistance includes: selecting a suitable testing instrument; providing training for laboratory technicians; establishing a simple quality control plan; and instructing staff on how to prepare frozen serum control materials suitable for assessing accuracy of lipid and lipoprotein testing.

Pitavastatin 4 mg Provides Significantly Greater Reduction in Remnant Lipoprotein Cholesterol Compared With Pravastatin 40 mg: Results from the Short-term Phase IV PREVAIL US Trial in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia.

PubMed

Miller, P Elliott; Martin, Seth S; Joshi, Parag H; Jones, Steven R; Massaro, Joseph M; D'Agostino, Ralph B; Sponseller, Craig A; Toth, Peter P

2016-03-01

Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that are implicated in atherosclerosis. We assessed the adequacy of pitavastatin 4 mg and pravastatin 40 mg in reducing atherogenic lipid parameters beyond LDL-C, in particular remnant lipoprotein cholesterol (RLP-C). From the Phase IV, multicenter, randomized, double-blind PREVAIL US (A Study of Pitavastatin 4 mg Vs. Pravastatin 40 mg in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia) trial, we examined lipoprotein cholesterol subfractions using Vertical Auto Profile testing and apolipoproteins B and A-I at baseline and 12 weeks. Participants with primary hyperlipidemia or mixed dyslipidemia had LDL-C levels of 130 to 220 mg/dL and triglyceride levels ≤ 400 mg/dL. In this post hoc analysis, changes in lipid parameters were compared by using ANCOVA. Lipoprotein subfraction data were available in 312 patients (pitavastatin, n = 157; pravastatin, n = 155). Pitavastatin promoted a greater reduction in RLP-C than pravastatin (-13.6 [8.7] vs -9.3 [9.5] mg/dL). Furthermore, the pitavastatin group reported greater reductions in both components of RLP-C (both, P < 0.001): intermediate-density lipoprotein cholesterol (-9.5 [6.3] vs -6.4 [6.6] mg/dL) and very low-density lipoprotein cholesterol subfraction 3 (-4.1 [3.5] vs -2.9 [3.8] mg/dL). There were also greater reductions in the major ratios of risk (apolipoprotein B/apolipoprotein A-I and total cholesterol/HDL-C) (both, P < 0.001). There were no significant changes in HDL-C, its subfractions, or natural log lipoprotein(a)-cholesterol. The mean age was 58.8 ± 8.9 years in the pitavastatin group and 57.0 ± 10.2 years in the pravastatin group. Compared with pravastatin 40 mg daily, pitavastatin 4 mg provided superior reductions in atherogenic lipid parameters beyond LDL-C, including RLP-C. Future studies are needed investigate the clinical implications of lowering directly measured RLP-C as the principal target. ClinicalTrials.gov identifier

Effect of Theobromine Consumption on Serum Lipoprotein Profiles in Apparently Healthy Humans with Low HDL-Cholesterol Concentrations

PubMed Central

Jacobs, Doris M.; Smolders, Lotte; Lin, Yuguang; de Roo, Niels; Trautwein, Elke A.; van Duynhoven, John; Mensink, Ronald P.; Plat, Jogchum; Mihaleva, Velitchka V.

2017-01-01

Scope: Theobromine is a major active compound in cocoa with allegedly beneficial effect on high-density-lipoprotein-cholesterol (HDL-CH). We have investigated the effect of theobromine (TB) consumption on the concentrations of triglyceride (TG) and cholesterol (CH) in various lipoprotein (LP) subclasses. Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 44 apparently healthy women and men (age: 60 ± 6 years, BMI: 29 ± 3 kg/m2) with low baseline HDL-CH concentrations consumed a drink supplemented with 500 mg/d theobromine for 4 weeks. TG and CH concentrations in 15 LP subclasses were predicted from diffusion-edited 1H NMR spectra of fasting serum. Results: The LP phenotype of the subjects was characterized by low CH concentrations in the large HDL particles and high TG concentrations in large VLDL and chylomicron (CM) particles, which clearly differed from a LP phenotype of subjects with normal HDL-CH. TB only reduced CH concentrations in the LDL particles by 3.64 and 6.79%, but had no effect on TG and CH in any of the HDL, VLDL and CM subclasses. Conclusion: TB was not effective on HDL-CH in subjects with a LP phenotype characterized by low HDL-CH and high TG in VLDL. PMID:28971099

Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids-4 (VLDL-4) study.

PubMed

Quispe, Renato; Manalac, Raoul J; Faridi, Kamil F; Blaha, Michael J; Toth, Peter P; Kulkarni, Krishnaji R; Nasir, Khurram; Virani, Salim S; Banach, Maciej; Blumenthal, Roger S; Martin, Seth S; Jones, Steven R

2015-09-01

High levels of the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio are associated with obesity, metabolic syndrome, and insulin resistance. We evaluated variability in the remaining lipid profile, especially remnant lipoprotein particle cholesterol (RLP-C) and its components (very low-density lipoprotein cholesterol subfraction 3 and intermediate-density lipoprotein cholesterol), with variability in the TG/HDL-C ratio in a very large study cohort representative of the general U.S. We examined data from 1,350,908 US individuals who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL) from 2009 to 2011. Demographic information other than age and sex was not available. Changes to the remaining lipid profile across percentiles of the TG/HDL-C ratio were quantified, as well as by three TG/HDL-C cut-off points previously proposed in the literature: 2.5 (male) and 2 (female), 3.75 (male) and 3 (female), and 3.5 (male and female). The mean age of our study population was 58.7 years, and 48% were men. The median TG/HDL-C ratio was 2.2. Across increasing TG/HDL-C ratios, we found steadily increasing levels of RLP-C, non-HDL-C and LDL density. Among the lipid parameters studied, RLP-C and LDL density had the highest relative increase when comparing individuals with elevated TG/HDL-C levels to those with lower TG/HDL-C levels using established cut-off points. Approximately 47% of TG/HDL-C ratio variance was attributable to RLP-C. In the present analysis, a higher TG/HDL-C ratio was associated with an increasingly atherogenic lipid phenotype, characterized by higher RLP-C along with higher non-HDL-C and LDL density. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function.

PubMed

Gillard, Baiba K; Raya, Joe L; Ruiz-Esponda, Raul; Iyer, Dinakar; Coraza, Ivonne; Balasubramanyam, Ashok; Pownall, Henry J

2013-07-01

HIV patients on antiretroviral therapy (HIV/ART) exhibit a unique atherogenic dyslipidemic profile with hypertriglyceridemia (HTG) and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. In the Heart Positive Study of HIV/ART patients, a hypolipidemic therapy of fenofibrate, niacin, diet, and exercise reduced HTG and plasma non-HDL cholesterol concentrations and raised plasma HDL cholesterol and adiponectin concentrations. We tested the hypothesis that HIV/ART HDL have abnormal structures and properties and are dysfunctional. Hypolipidemic therapy reduced the TG contents of low-density lipoprotein and HDL. At baseline, HIV/ART low-density lipoproteins were more triglyceride (TG)-rich and HDL were more TG- and cholesteryl ester-rich than the corresponding lipoproteins from normolipidemic (NL) subjects. Very-low-density lipoproteins, low-density lipoprotein, and HDL were larger than the corresponding lipoproteins from NL subjects; HIV/ART HDL were less stable than NL HDL. HDL-[(3)H]cholesteryl ester uptake by Huh7 hepatocytes was used to assess HDL functionality. HIV/ART plasma were found to contain significantly less competitive inhibition activity for hepatocyte HDL-cholesteryl ester uptake than NL plasma were found to contain (P<0.001). Compared with NL subjects, lipoproteins from HIV/ART patients are larger and more neutral lipid-rich, and their HDL are less stable and less receptor-competent. On the basis of this work and previous studies of lipase activity in HIV, we present a model in which plasma lipolytic activities or hepatic cholesteryl ester uptake are impaired in HIV/ART patients. These findings provide a rationale to determine whether the distinctive lipoprotein structure, properties, and function of HIV/ART HDL predict atherosclerosis as assessed by carotid artery intimal medial thickness.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

PubMed

Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis C; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond T; Fernández-Hernando, Carlos; Kaplan, Lee M; Bernards, Andre; Gerszten, Robert E; Näär, Anders M

2015-11-01

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator.

PubMed

Jiang, Huajun; Zhang, Jin; Du, Yu; Jia, Xiaojian; Yang, Fan; Si, Shuyi; Wang, Li; Hong, Bin

2015-12-01

Low-density lipoprotein receptor (LDLR) mediates endocytosis of LDL particles and is important in maintaining plasma cholesterol levels, thus its expression is under extensive regulation at multiple levels, including transcriptional and posttranscriptional regulation by transcription factors (TFs) and RNA-binding proteins (RBPs). Here, we identified microRNA-185 (miR-185) as a novel direct posttranscriptional regulator of LDLR and an indirect LDLR modulator through KSRP in hepatic cells. Using quantitative real-time PCR (qPCR), we detected the effect of predicted LDLR-targeting miRNAs and found that overexpression of miR-185 repressed LDLR expression and LDL uptake in HepG2 cells by 62.4 ± 6.0% (p = 7.0 × 10(-5)) and 32.5 ± 6.0% (p = 7.7 × 10(-4)) respectively, through directly targeting LDLR 3'UTR. Unexpectedly, the antisense inhibitor of miR-185 had similar repression effect on LDLR although it reduced the association of endogenous miR-185 with LDLR mRNA. Further experiments revealed that KH-type splicing regulatory protein (KSRP), one of the LDLR-destabilizing RBPs, is also a target of miR-185. KSRP silencing reversed the repression effects of miR-185-inhibitor on LDLR. Thus miR-185 regulates LDLR expression not only through directly targeting but also by a RBP-involved indirect pathway. Finally, the in vivo results showed that miR-185-inhibitor upregulated hepatic LDLR expression and correlated with a decrease in plasma cholesterol level and arterial plaque area in ApoE KO mice. These findings reveal that miR-185 controls cholesterol homeostasis as a key posttranscriptional LDLR modulator in hepatic cells, providing novel insight into the regulatory mechanism for LDLR expression and the anti-atherosclerosis effect of miR-185-inhibitor. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

MicroRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis

PubMed Central

Meiler, Svenja; Baumer, Yvonne; Toulmin, Emma; Seng, Kosal; Boisvert, William A.

2014-01-01

Objective Macrophage foam cell formation is a key feature of atherosclerosis. Recent studies have shown that specific microRNAs (miRs) are regulated in modified low-density lipoprotein (LDL)- treated macrophages, which can affect the cellular cholesterol homeostasis. Undertaking a genome-wide screen of microRNAs regulated in primary macrophages by modified LDL, miR-302a emerged as a potential candidate that may play a key role in macrophage cholesterol homeostasis. Approach and Results The objective of this study was to assess the involvement of miR-302a in macrophage lipid homeostasis and if it can influence circulating lipid levels and atherosclerotic development when it is inhibited in a murine atherosclerosis model. We found that transfection of primary macrophages with either miR-302a or anti-miR-302a regulated the expression of ATP-binding cassette (ABC) transporter ABCA1 mRNA and protein. Luciferase reporter assays showed that miR-302a repressed the 3′UTR activity of mouse Abca1 by 48% and human ABCA1 by 45%. Additionally, transfection of murine macrophages with miR-302a attenuated cholesterol efflux to apolipoprotein A-1 (apoA-1) by 38%. Long-term in vivo administration of anti-miR-302a to mice with LDL receptor deficiency (Ldlr−/−) fed an atherogenic diet led to an increase in ABCA1 in the liver and aorta as well as an increase in circulating plasma HDL levels by 35% compared with that of control mice. The anti-miR-302a-treated mice also displayed reduced atherosclerotic plaque size by approximately 25% as well as a more stable plaque morphology with reduced signs of inflammation. Conclusions These studies identify miR-302a as a novel modulator of cholesterol efflux and a potential therapeutic target for suppressing atherosclerosis. PMID:25524771

Facts about...Blood Cholesterol. Revised.

ERIC Educational Resources Information Center

National Heart, Lung, and Blood Inst. (DHHS/NIH), Bethesda, MD.

This fact sheet on blood cholesterol examines the connection between cholesterol and heart disease, lists risk factors for heart disease that can and cannot be controlled, points out who can benefit from lowering blood cholesterol, distinguishes between blood and dietary cholesterol, describes low density lipoprotein and high density lipoprotein…

The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol Rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH).

PubMed

2011-03-01

The aim of this study was to test the hypothesis that patients with atherosclerotic cardiovascular (CV) disease optimally treated on a statin but with residual atherogenic dyslipidemia (low high-density lipoprotein cholesterol [HDL-C] and high triglycerides) will benefit from addition of niacin with fewer CV events compared with placebo. Statin monotherapy trials have found 25%-35% CV risk reduction relative to placebo, leaving significant residual risk. Patients with atherogenic dyslipidemia have substantially increased CV risk. Participants were men and women with established CV disease and atherogenic dyslipidemia. Lipid entry criteria varied by gender and statin dose at screening. All participants received simvastatin (or simvastatin plus ezetimibe) at a dose sufficient to maintain low-density lipoprotein cholesterol (LDL-C) 40-80 mg/dL (1.03-2.07 mmol/L). Participants were randomized to extended-release niacin or matching placebo. The primary end point was time to occurrence of the first of the following: coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. This event-driven trial will have 85% power to show a 25% reduction in primary event frequency after 850 patients have experienced a primary outcome event. AIM-HIGH completed enrollment in April 2010. Follow-up is expected to continue through 2012. AIM-HIGH was designed to determine whether treating residual dyslipidemia with niacin further reduces cardiovascular events in patients with CV disease on a statin at target levels of low-density lipoprotein cholesterol. Copyright © 2011 Mosby, Inc. All rights reserved.

Evidence That Chromium Modulates Cellular Cholesterol Homeostasis and ABCA1 Functionality Impaired By Hyperinsulinemia

PubMed Central

Sealls, Whitney; Penque, Brent A.; Elmendorf, Jeffrey S.

2011-01-01

Objective Trivalent chromium (Cr3+) is an essential micronutrient. Findings since the 1950s suggest that Cr3+ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr3+. Method and Results High-density lipoprotein cholesterol generation in 3T3-L1 adipocytes, rendered ineffective by hyperinsulinemia, known to accompany disorders of lipid metabolism was corrected by Cr3+. Mechanistically, Cr3+ reversed hyperinsulinemia-induced cellular cholesterol accrual and associated defects in cholesterol transporter ABCA1 trafficking and apolipoprotein A1-mediated cholesterol efflux. Moreover, direct activation of AMP-activated protein kinase (AMPK), known to be activated by Cr3+, and/or inhibition of hexosamine biosynthesis pathway (HBP) activity, known to be elevated by hyperinsulinemia, mimics Cr3+ action. Conclusion These findings suggest a mechanism of Cr3+ action that fits with long-standing claims of its role in cholesterol homeostasis. Furthermore, these data implicate a mechanistic basis for the coexistence of dyslipidemia with hyperinsulinemia. PMID:21311039

Association of Cholesterol Efflux Capacity With Clinical Features of Metabolic Syndrome: Relevance to Atherosclerosis.

PubMed

Gall, Julie; Frisdal, Eric; Bittar, Randa; Le Goff, Wilfried; Bruckert, Eric; Lesnik, Philippe; Guerin, Maryse; Giral, Philippe

2016-11-23

The contribution of high-density lipoprotein to cardiovascular benefit is closely linked to its role in the cellular cholesterol efflux process; however, various clinical and biochemical variables are known to modulate the overall cholesterol efflux process. The aim of this study was to evaluate the extent to which clinical and biological anomalies associated with the establishment of the metabolic syndrome modulate cholesterol efflux capacity and contribute to development of atherosclerosis. This study involved patients (n=1202) displaying atherogenic dyslipidemia in primary prevention who were referred to our prevention center. Among these patients, 25% presented at least 3 criteria of the metabolic syndrome, as defined by the National Cholesterol Education Program Adult Treatment Panel III. We measured the capacity of 40-fold diluted serum to mediate cholesterol efflux from cholesterol-loaded human THP-1 macrophages. Cholesterol efflux capacity was reduced progressively by 4% to 11% (P<0.0001) as a function of the increasing number of coexisting criteria for the metabolic syndrome from 1 to 5. This observation was primarily related to reductions in scavenger receptor class B member 1 and ATP binding cassette subfamily G member 1-dependent efflux. Multivariate analyses indicate that serum efflux capacity was significantly associated with established metabolic syndrome (odds ratio 0.45; 95% CI 0.28-0.72; P=0.009) independent of age, low-density lipoprotein cholesterol, status with regard to lipid-lowering therapy, smoking status, and alcohol consumption. Our study revealed that individual criteria of metabolic syndrome are closely related synergistically to cholesterol efflux capacity. In addition, established metabolic syndrome and cholesterol efflux capacity were independently associated with clinical features of atherosclerosis. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

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

PubMed Central

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.

2014-01-01

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

FADS1 genetic variability interacts with dietary α-linolenic acid intake to affect serum non-HDL-cholesterol concentrations in European adolescents.

PubMed

Dumont, Julie; Huybrechts, Inge; Spinneker, Andre; Gottrand, Frédéric; Grammatikaki, Evangelia; Bevilacqua, Noemi; Vyncke, Krishna; Widhalm, Kurt; Kafatos, Anthony; Molnar, Denes; Labayen, Idoia; Gonzalez-Gross, Marcela; Amouyel, Philippe; Moreno, Luis A; Meirhaeghe, Aline; Dallongeville, Jean

2011-07-01

Two rate-limiting enzymes in PUFA biosynthesis, Δ5- and Δ6-desaturases, are encoded by the FADS1 and FADS2 genes, respectively. Genetic variants in the FADS1-FADS2 gene cluster are associated with changes in plasma concentrations of PUFA, HDL- and LDL-cholesterol, and TG. However, little is known about whether dietary PUFA intake modulates these associations, especially in adolescents. We assessed whether dietary linoleic acid (LA) or α-linolenic acid (ALA) modulate the association between the FADS1 rs174546 polymorphism and concentrations of PUFA, other lipids, and lipoproteins in adolescents. Dietary intakes of LA and ALA, FADS1 rs174546 genotypes, PUFA levels in serum phospholipids, and serum concentrations of TG, cholesterol, and lipoproteins were determined in 573 European adolescents from the HELENA study. The sample was stratified according to the median dietary LA (≤9.4 and >9.4 g/d) and ALA (≤1.4 and >1.4 g/d) intakes. The associations between FADS1 rs174546 and concentrations of PUFA, TG, cholesterol, and lipoproteins were not affected by dietary LA intake (all P-interaction > 0.05). Similarly, the association between the FADS1 rs174546 polymorphism and serum phospholipid concentrations of ALA or EPA was not modified by dietary ALA intake (all P-interaction > 0.05). In contrast, the rs174546 minor allele was associated with lower total cholesterol concentrations (P = 0.01 under the dominant model) and non-HDL-cholesterol concentrations (P = 0.02 under the dominant model) in the high-ALA-intake group but not in the low-ALA-intake group (P-interaction = 0.01). These results suggest that dietary ALA intake modulates the association between FADS1 rs174546 and serum total and non-HDL-cholesterol concentrations at a young age.

Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol.

PubMed

Wu, Kuan-Ta; Kuo, Po-Lin; Su, Shih-Bin; Chen, Yi-Yu; Yeh, Ming-Lum; Huang, Ching-I; Yang, Jeng-Fu; Lin, Chia-I; Hsieh, Meng-Hsuan; Hsieh, Ming-Yen; Huang, Chung-Feng; Lin, Wen-Yi; Yu, Ming-Lung; Dai, Chia-Yen; Wang, Hsien-Yi

2016-01-01

Limited data support the notion that lipid ratios are risk factors for nonalcoholic fatty liver disease (NAFLD). We evaluated the association between lipid ratios and NAFLD. This was a large population, cross-sectional, retrospective study. Data on NAFLD severity, blood pressure, fasting glucose, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels were obtained from 44,767 examinees at single health checkup center. The enrollees were stratified into four subgroups based on their TC/HDL-C and TG/HDL-C ratios. We used multivariate analyses to evaluate the odds between lipid ratios and NAFLD. The prevalence rate of fatty liver in this study was 53.76%. In the baseline subgroup with the lowest TC/HDL-C and TG/HDL-C ratios, the prevalence of NAFLD, hypertension, and diabetes was lower than that of the other three subgroups. Patients with higher lipid ratios had a significantly greater risk for advanced NAFLD. Adults with high TC/HDL-C or TG/HDL-C ratios, or both, have a greater risk for NAFLD, especially advanced NAFLD. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Effective reduction of LDL cholesterol by indigenous plant product.

PubMed

Bhardwaj, P K; Dasgupta, D J; Prashar, B S; Kaushal, S S

1994-03-01

A herbal powder containing guar gum, methi, tundika and meshasringi was administered to 30 control and 30 type 2 (non-insulin dependent) diabetes mellitus patients for a month. Total serum cholesterol and its fractions eg, high density lipoprotein, low density lipoproteins, very low density lipoproteins and serum triglyceride were determined before and after the trial period. Total and low density lipoprotein (LDL) cholesterols were reduced significantly after the therapy. There were no significant changes in high density lipoproteins (HDL), very low density lipoproteins (VLDL) or triglyceride levels. Side-effects eg, mild flatulence and looseness of bowel were noticed in less than 40% cases.

Cholesterol Metabolism in CKD

PubMed Central

Reiss, Allison B.; Voloshyna, Iryna; DeLeon, Joshua; Miyawaki, Nobuyuki; Mattana, Joseph

2015-01-01

Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely impacts lipid balance. Dyslipidemia in CKD is characterized by elevated triglycerides and high density lipoprotein that is both decreased and dysfunctional. This dysfunctional high density lipoprotein becomes pro-inflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglycerides result primarily from defective clearance. The weak association between low density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and pre-clinical evidence of the impact of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored. PMID:26337134

APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation- and Meta-Analyses of 137 895 Individuals.

PubMed

Wulff, Anders B; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2018-03-01

Loss-of-function mutations in APOC3 associate with low remnant cholesterol levels and low risk of ischemic vascular disease (IVD). Because some studies show an additional association with low levels of low-density lipoprotein cholesterol (LDL-C), low LDL-C may explain the low risk of IVD in APOC3 loss-of-function heterozygotes. We tested to what extent the low risk of IVD in APOC3 loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C. In APOC3 loss-of-function heterozygotes versus noncarriers, we first determined remnant cholesterol and LDL-C levels in meta-analyses of 137 895 individuals. Second, we determined whether the association with LDL-C was masked by lipid-lowering therapy. Finally, using mediation analysis, we determined the fraction of the low risk of IVD and ischemic heart disease mediated by remnant cholesterol and LDL-C. In meta-analyses, remnant cholesterol was 43% lower (95% confidence interval, 40%-47%), and LDL-C was 4% lower (1%-6%) in loss-of-function heterozygotes (n=776) versus noncarriers. In the general population, LDL-C was 3% lower in loss-of-function heterozygotes versus noncarriers, 4% lower when correcting for lipid-lowering therapy, and 3% lower in untreated individuals ( P values, 0.06-0.008). Remnant cholesterol mediated 37% of the observed 41% lower risk of IVD and 54% of the observed 36% lower risk of ischemic heart disease; corresponding values mediated by LDL-C were 1% and 2%. The low risk of IVD observed in APOC3 loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL-C to IVD risk was not masked by lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk. © 2018 American Heart Association, Inc.

Cholesterol treatment guidelines update.

PubMed

Safeer, Richard S; Ugalat, Prabha S

2002-03-01

Hypercholesterolemia is one of the major contributors to atherosclerosis and coronary heart disease in our society. The National Cholesterol Education Program of the National Institutes of Health has created a set of guidelines that standardize the clinical assessment and management of hypercholesterolemia for practicing physicians and other professionals in the medical community. In May 2001, the National Cholesterol Education Program released its third set of guidelines, reflecting changes in cholesterol management since their previous report in 1993. In addition to modifying current strategies of risk assessment, the new guidelines stress the importance of an aggressive therapeutic approach in the management of hypercholesterolemia. The major risk factors that modify low-density lipoprotein goals include age, smoking status, hypertension, high-density lipoprotein levels, and family history. The concept of "CHD equivalent" is introduced-conditions requiring the same vigilance used in patients with coronary heart disease. Patients with diabetes and those with a 10-year cardiac event risk of 20 percent or greater are considered CHD equivalents. Once low-density lipoprotein cholesterol is at an accepted level, physicians are advised to address the metabolic syndrome and hypertriglyceridemia.

Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body.

PubMed

Yokoyama, S

2000-12-15

Most mammalian somatic cells are unable to catabolize cholesterol and therefore need to export it in order to maintain sterol homeostasis. This mechanism may also function to reduce excessively accumulated cholesterol, which would thereby contribute to prevention or cure of the initial stage of atherosclerotic vascular lesion. High-density lipoprotein (HDL) has been believed to play a main role in this reaction based on epidemiological evidence and in vitro experimental data. At least two independent mechanisms are identified for this reaction. One is non-specific diffusion-mediated cholesterol 'efflux' from cell surface. Cholesterol molecules desorbed from cells can be trapped by various extracellular acceptors including various lipoproteins and albumin, and extracellular cholesterol esterification mainly on HDL may provide a driving force for the net removal of cell cholesterol by maintaining a cholesterol gradient between lipoprotein surface and cell membrane. The other is apolipoprotein-mediated process to generate new HDL by removing cellular phospholipid and cholesterol. The reaction is initiated by the interaction of lipid-free or lipid-poor helical apolipoproteins with cellular surface resulting in assembly of HDL particles with cellular phospholipid and incorporation of cellular cholesterol into the HDL being formed. Thus, HDL has dual functions as an active cholesterol acceptor in the diffusion-mediated pathway and as an apolipoprotein carrier for the HDL assembly reaction. The impairment of the apolipoprotein-mediated reaction was found in Tangier disease and other familial HDL deficiencies to strongly suggest that this is a main mechanism to produce plasma HDL. The causative mutations for this defect was identified in ATP binding cassette transporter protein A1, as a significant step for further understanding of the reaction and cholesterol homeostasis.

Peroxisome proliferator-activated receptor gamma co-activator 1 gene Gly482Ser polymorphism is associated with the response of low-density lipoprotein cholesterol concentrations to exercise training in elderly Japanese.

PubMed

Tobina, Takuro; Mori, Yukari; Doi, Yukiko; Nakayama, Fuki; Kiyonaga, Akira; Tanaka, Hiroaki

2017-09-01

Muscle peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1)α gene expression is influenced by the Gly482Ser gene polymorphism, which is a candidate genetic risk factor for diabetes mellitus and obesity. This study investigated the effects of PGC-1 gene Gly482Ser polymorphisms on alterations in glucose and lipid metabolism induced by exercise training. A 12-week intervention study was performed for 119 participants who were more than 65 years of age and completed exercise training at lactate threshold intensity. Total cholesterol and low-density lipoprotein cholesterol were significantly reduced in Gly/Gly but not in Gly/Ser and Ser/Ser participants after exercise. The Gly/Gly genotype of the PGC-1 gene Gly482Ser polymorphism influences the effects of moderate-intensity exercise training on low-density lipoprotein cholesterol and total cholesterol concentrations in older people.

Dyslipidemia in subclinical hypothyroidism requires assessment of small dense low density lipoprotein cholesterol (sdLDL-C).

PubMed

Saric, Maida Seferovic; Jurasic, Miljenka-Jelena; Sovic, Slavica; Kranjcec, Bojana; Glivetic, Tatjana; Demarin, Vida

2017-09-26

Usually both hypothyroidism and hyperthyroidism are related to the cardiovascular and cerebrovascular disease development. The relationship between subclinical hypothyroidism has been widely investigated but the findings remain controversial. The aim of the present study was to evaluate the lipid profile in patients with subclinical hypothyroidism (SHypo) in comparison to controls and to determine the association of SHypo and dyslipidemia in attempt to find importance of small dense low-density lipoprotein cholesterol (sdLDL-C) in atherosclerosis. In this study we included 100 women, aged 30 to 70 years that were divided into subgroups according to their age. According to the values of levels of thyroid hormones they were divided into euthyroid (control) group (n = 64) and (newly discovered) subclinical hypothyroidism (SHypo) group (n = 36). A high-sensitivity C-reactive protein (hs-CRP) and lipid profile, including small dense low-density lipoprotein cholesterol (sdLDL-C) were determined. Body weight and height were measured and BMI calculated. History of the current illness, medication, alcohol consumption and cigarettes smoking were noted. Changed lipid profile as well as elevated triglycerides and sdLDL-C were observed in the group with subclinical hypothyroidism compared to the control group. It is important to determine serum lipid levels, especially serum sdLDL-C levels at an early stage of subclinical hypothyroidism, since they represent atherogenic LDL particles and are better indicators for dyslipidaemia in subclinical hypothyroidism and the development of atherosclerosis with potential complications such as cardiovascular and cerebrovascular diseases.

The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis*

PubMed Central

Fryer, Lee G. D.; Jones, Bethan; Duncan, Emma J.; Hutchison, Claire E.; Ozkan, Tozen; Williams, Paul A.; Alder, Olivia; Nieuwdorp, Max; Townley, Anna K.; Mensenkamp, Arjen R.; Stephens, David J.; Dallinga-Thie, Geesje M.; Shoulders, Carol C.

2014-01-01

Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions. PMID:24338480

Structure of Serum Amyloid A Suggests a Mechanism for Selective Lipoprotein Binding and Functions: SAA as a Hub in Macromolecular Interaction Networks

PubMed Central

Frame, Nicholas M.; Gursky, Olga

2016-01-01

Serum amyloid A is a major acute-phase plasma protein that modulates innate immunity and cholesterol homeostasis. We combine sequence analysis with x-ray crystal structures to postulate that SAA acts as an intrinsically disordered hub mediating interactions among proteins, lipids and proteoglycans. A structural model of lipoprotein-bound SAA monomer is proposed wherein two α-helices from the N-domain form a concave hydrophobic surface that binds lipoproteins. A C-domain, connected to the N-domain via a flexible linker, binds polar/charged ligands including cell receptors, bridging them with lipoproteins and re-routing cholesterol transport. Our model is supported by the SAA cleavage in the inter-domain linker to generate the 1–76 fragment deposited in reactive amyloidosis. This model sheds new light on functions of this enigmatic protein. PMID:26918388

What Are High Blood Cholesterol and Triglycerides?

MedlinePlus

ANSWERS by heart Lifestyle + Risk Reduction Cholesterol What Are High Blood Cholesterol and Triglycerides? Cholesterol travels to the body’s cells through the bloodstream by way of lipoproteins (LDL and ...

Impact of Dietary Calcium Supplement on Circulating Lipoprotein Concentrations and Atherogenic Indices in Overweight and Obese Individuals: A Systematic Review.

PubMed

Heshmati, Javad; Sepidarkish, Mahdi; Namazi, Nazli; Shokri, Fatemeh; Yavari, Mahsa; Fazelian, Siavash; Khorshidi, Masoud; Shidfar, Farzad

2018-03-21

Dyslipidemia is the main risk factor for developing cardiovascular disease. There are discrepancies in the effects of calcium supplementation on modulation of lipid status. Therefore, we aimed to summarize the effects of dietary calcium supplement on circulating lipoprotein concentrations and atherogenic indices in overweight and obese individuals. We conducted a systematic literature search from 2000 until July 2016. PubMed, Scopus, Cochran Library, and ISI Web of Science databases were searched for clinical trials written in English. Placebo controlled clinical trials on calcium or calcium with vitamin D supplement in overweight and obese indiciduals were considered. Finally, 11 clinical trials met the criteria and were included. Most studies (n = 9) evaluated Ca/D co-supplementation. Positive effects of calcium supplementation alone or with vitamin D were as follows: serum levels of total cholesterol (TC; n = 1), triglyceride (TG) concentrations (n = 1), serum levels of low-density lipoprotein cholesterol (LDL-C; n = 5) and high-density lipoprotein cholesterol (HDL-C; n = 3). Seven clinical trials reported atherogenic indices and three of them demonstrated beneficial effects of calcium supplementation on at least one atherogenic index. Calcium supplementation may not be helpful to reduce serum levels of TC and TG in overweight and obese individuals. However, it may modulate LDL-C and HDL-C concentration. More studies are warranted to clarify the effects of calcium supplementation on each atherogenic index.

Maturation of high-density lipoproteins

PubMed Central

Shih, Amy Y.; Sligar, Stephen G.; Schulten, Klaus

2009-01-01

Human high-density lipoproteins (HDLs) are involved in the transport of cholesterol. The mechanism by which HDL assembles and functions is not well understood owing to a lack of structural information on circulating spherical HDL. Here, we report a series of molecular dynamics simulations that describe the maturation of discoidal HDL into spherical HDL upon incorporation of cholesterol ester as well as the resulting atomic level structure of a mature circulating spherical HDL particle. Sixty cholesterol ester molecules were added in a stepwise fashion to a discoidal HDL particle containing two apolipoproteins wrapped around a 160 dipalmitoylphosphatidylcholine lipid bilayer. The resulting matured particle, captured in a coarse-grained description, was then described in a consistent all-atom representation and analysed in chemical detail. The simulations show that maturation results from the formation of a highly dynamic hydrophobic core comprised of cholesterol ester surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation as seen in the discoidal HDL particle, but with flexible N- and C-terminal helices and a central region stabilized by salt bridges. In the otherwise flexible lipoproteins, a less mobile central region provides an ideal location to bind lecithin cholesterol acyltransferase, the key enzyme that converts cholesterol to cholesterol ester during HDL maturation. PMID:19570799

Cholesterol values in free-ranging gorillas (Gorilla gorilla gorilla and Gorilla beringei) and Bornean orangutans (Pongo pygmaeus).

PubMed

Schmidt, Debra A; Ellersieck, Mark R; Cranfield, Michael R; Karesh, William B

2006-09-01

Cholesterol concentrations in captive gorillas and orangutans vary widely within species and average approximately 244 mg/dl for gorillas and 169 mg/dl for orangutans as published previously. The International Species Inventory System reports higher concentrations of 275 and 199 mg/dl for gorillas and orangutans, respectively. It is unknown whether these values were typical, influenced by captive management, or both. To answer this question, banked serum samples from free-ranging mountain gorillas (Gorilla beringei), western lowland gorillas (Gorilla gorilla gorilla), and Bornean orangutans (Pongo pygmaeus) were analyzed for total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol concentrations. Mountain gorillas did not differ significantly from free-ranging western lowland gorillas in cholesterol, triglyceride, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol concentrations, indicating mountain gorilla values could be a model for western lowland gorillas. Captive gorilla total cholesterol and low-density lipoprotein cholesterol concentrations were significantly higher (P < 0.05) than in free-ranging groups. Triglyceride concentrations for captive gorillas were significantly higher (P < 0.05) than the male mountain and western lowland gorillas, but they were not significantly different from the female mountain gorillas. Captive orangutan total cholesterol concentrations were only higher (P < 0.05) than the free-ranging female orangutans, whereas captive orangutan low-density lipoprotein cholesterol concentrations were significantly higher (P < 0.05) than both free-ranging male and female orangutans. Calculated and measured low-density lipoprotein cholesterol concentrations were compared for all free-ranging animals and were significantly different (P < 0.05) for all groups, indicating Friedewald's equation for calculating low-density lipoprotein cholesterol is not appropriate for

Ezetimibe Increases Endogenous Cholesterol Excretion in Humans.

PubMed

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Ostlund, Richard E

2017-05-01

Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool. In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d 7 in a lipid emulsion and dietary cholesterol with cholesterol-d 5 and sitostanol-d 4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, P <0.0001) and low-density lipoprotein cholesterol 19.8±1.9% ( P =0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% ( P <0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% ( P <0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% ( P =0.0096). Fecal bile acids were unchanged. Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758. © 2017 American Heart Association, Inc.

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

Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations

PubMed Central

Ma, Li; Brautbar, Ariel; Boerwinkle, Eric; Sing, Charles F.

2012-01-01

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P c = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene–gene interaction in the European American cohorts from the Framingham Heart Study (P c = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P c = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P c = 0.004) and in the Hispanic American sample from MESA (P c = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene–gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations. PMID:22654671

Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis.

PubMed

Hourcade-Potelleret, F; Laporte, S; Lehnert, V; Delmar, P; Benghozi, Renée; Torriani, U; Koch, R; Mismetti, P

2015-06-01

Epidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer protein (CETP) inhibitors. To assess alternative methods to predict clinical response of CETP inhibitors. Meta-regression analysis on raising HDL-C drugs (statins, fibrates, niacin) in randomised controlled trials. 51 trials in secondary prevention with a total of 167,311 patients for a follow-up >1 year where HDL-C was measured at baseline and during treatment. The meta-regression analysis showed no significant association between change in HDL-C (treatment vs comparator) and log risk ratio (RR) of clinical endpoint (non-fatal myocardial infarction or cardiac death). CETP inhibitors data are consistent with this finding (RR: 1.03; P5-P95: 0.99-1.21). A prespecified sensitivity analysis by drug class suggested that the strength of relationship might differ between pharmacological groups. A significant association for both statins (p<0.02, log RR=-0.169-0.0499*HDL-C change, R(2)=0.21) and niacin (p=0.02, log RR=1.07-0.185*HDL-C change, R(2)=0.61) but not fibrates (p=0.18, log RR=-0.367+0.077*HDL-C change, R(2)=0.40) was shown. However, the association was no longer detectable after adjustment for low-density lipoprotein cholesterol for statins or exclusion of open trials for niacin. Meta-regression suggested that CETP inhibitors might not influence coronary risk. The relation between change in HDL-C level and clinical endpoint may be drug dependent, which limits the use of HDL-C as a surrogate marker of coronary events. Other markers of HDL function may be more relevant. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Novel function of lecithin-cholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation.

PubMed

Goyal, J; Wang, K; Liu, M; Subbaiah, P V

1997-06-27

Although the major function of lecithin-cholesterol acyltransferase (LCAT) is cholesterol esterification, our previous studies showed that it can also hydrolyze platelet-activating factor (PAF). Because of the structural similarities between PAF and the truncated phosphatidylcholines (polar PCs) generated during lipoprotein oxidation, we investigated the possibility that LCAT may also hydrolyze polar PCs to lyso-PC during the oxidation of plasma. PAF acetylhydrolase (PAF-AH), which is known to hydrolyze polar PCs in human plasma, was completely inhibited by 0.2 mM p-aminoethyl benzenesulfonyl fluoride (Pefabloc), a new serine esterase inhibitor, which had no effect on LCAT at this concentration. On the other hand, 1 mM diisopropylfluorophosphate (DFP) completely inhibited LCAT but had no effect on PAF-AH. Polar PC accumulation during the oxidation of plasma increased by 44% in the presence of 0.2 mM Pefabloc and by 30% in the presence of 1 mM DFP. The formation of lyso-PC was concomitantly inhibited by both of the inhibitors. The combination of the two inhibitors resulted in the maximum accumulation of polar PCs, suggesting that both PAF-AH and LCAT are involved in their breakdown. Oxidation of chicken plasma, which has no PAF-AH activity, also resulted in the formation of lyso-PC from the hydrolysis of polar PC, which was inhibited by DFP. Polar PCs, either isolated from oxidized plasma or by oxidation of labeled synthetic PCs, were hydrolyzed by purified LCAT, which had no detectable PAF-AH activity. These results demonstrate a novel function for LCAT in the detoxification of polar PCs generated during lipoprotein oxidation, especially when the PAF-AH is absent or inactivated.

Association between high-density lipoprotein cholesterol level and pulmonary function in healthy Korean adolescents: the JS high school study.

PubMed

Park, Ji Hye; Mun, Seyeon; Choi, Dong Phil; Lee, Joo Young; Kim, Hyeon Chang

2017-12-11

Accumulating evidence suggests that high-density lipoprotein (HDL) cholesterol is associated with pulmonary function and pulmonary disorders. The aim of this study was to evaluate the association between HDL cholesterol and pulmonary function in healthy adolescents. This cross-sectional study was based on data collected for the JS High School study. The analysis included 644 adolescents (318 male and 326 female) aged 15-16 years old and free from asthma or chronic obstructive pulmonary disease. Fasting blood samples were collected for hematologic and biochemical assessment. Forced vital capacity volume (FVC) and forced expiratory volume in the 1 s (FEV1) were measured using dry-rolling-seal spirometry. The associations between HDL cholesterol and pulmonary function were analyzed using multiple linear regression models. Among male adolescents, an increase of 1.0 mg/dL in HDL cholesterol was associated with 10 mL decrease in FVC (p = 0.013) and FEV1 (p = 0.013) after adjusting for age, height, weight, alcohol drinking, smoking, physical activity, systolic blood pressure, total cholesterol, triglyceride, and monthly household income. Percent predicted values of FVC (p = 0.036) and FEV1 (p = 0.017) were also inversely associated with HDL cholesterol. However, among female adolescents, HDL cholesterol level was not significantly associated with absolute or percent predictive value of FVC and FEV1. Higher HDL cholesterol level may be associated with decreased pulmonary function among healthy male adolescents. The sex differences observed in the association between HDL cholesterol and pulmonary function need further investigation.

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

PubMed

Moghadasian, Mohammed H; Zhao, Ruozhi; Ghazawwi, Nora; Le, Khuong; Apea-Bah, Franklin B; Beta, Trust; Shen, Garry X

2017-10-18

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

Triglyceride Treatment in the Age of Cholesterol Reduction

PubMed Central

Agrawal, Nidhi; Corradi, Patricia Freitas; Gumaste, Namrata; Goldberg, Ira J.

2017-01-01

Cholesterol reduction has markedly reduced major cardiovascular disease (CVD) events and shown regression of atherosclerosis in some studies. However, CVD has for decades also been associated with increased levels of circulating triglyceride (TG)-rich lipoproteins. Whether this is due to a direct toxic effect of these lipoproteins on arteries or whether this is merely an association is unresolved. More recent genetic analyses have linked genes that modulate TG metabolism with CVD. Moreover, analyses of subgroups of hypertriglyceridemic (HTG) subjects in clinical trials using fibric acid drugs have been interpreted as evidence that TG reduction reduces CVD events. This review will focus on how HTG might cause CVD, whether TG reduction makes a difference, what pathophysiological defects cause HTG, and what options are available for treatment. PMID:27544319

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans.

PubMed

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Dávila-Román, Victor G; Ostlund, Richard E

2017-12-01

Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis. Cholesterol metabolism and carotid intima-media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d 7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d 5 and the nonabsorbable stool marker sitostanol-d 4 . Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima-media thickness was negatively correlated with fecal excretion of endogenous cholesterol ( r =-0.426; P <0.0001), total cholesterol ( r =-0.472; P ≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool ( r =-0.343; P =0.0012) and was positively correlated with percent cholesterol absorption ( r =+0.279; P =0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant ( P =0.0008). Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima-media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate

Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not contribute to low levels of high-density lipoprotein cholesterol

PubMed Central

Dastani, Zari; Ruel, Isabelle L; Engert, James C; Genest, Jacques; Marcil, Michel

2007-01-01

Background Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL) cholesterol. Methods Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R) and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (< 5th percentile for age and gender-matched subjects). Control subjects (n = 230) had an HDL-cholesterol level > the 25th percentile. Results For G1522A the frequency of the G and A alleles were 75.2% and 24.8% respectively in controls, compared to 78.6% and 21.4% in subjects with low HDL-cholesterol (p = 0.317). The frequency of 6 and 7 hexanucleotide repeats was 46.2% and 46.6% respectively in controls, compared to 45.6% and 49.1% in subjects with low HDL-cholesterol (p = 0.619). Ten different haplotypes were observed in cases and controls. Overall haplotype frequencies in cases and controls were not significantly different. Conclusion These results suggest that the two common coding variants at the SMPD1 gene locus are not associated with low HDL-cholesterol levels in the French Canadian population. PMID:18088425

Non-high-density lipoprotein cholesterol on the risks of stroke: a result from the Kailuan study.

PubMed

Wu, Jianwei; Chen, Shengyun; Zhou, Yong; Wang, Chunxue; Wang, Anxin; Zhang, Qian; Gao, Xiang; Hu, Haitao; Wu, Shouling; Zhao, Xingquan

2013-01-01

To prospectively explore the association between non-high-density lipoprotein cholesterol (non-HDLC) and the risks of stroke and its subtypes. A total of 95,916 participants (18-98 years old; 76,354 men and 19,562 women) from a Chinese urban community who were free of myocardial infarction and stroke at baseline time point (2006-2007) were eligible and enrolled in the study. The serum non-HDLC levels of participants were determined by subtracting the high-density lipoprotein cholesterol (HDLC) from total serum cholesterol. The primary outcome was the first occurrence of stroke, which was diagnosed according to the World Health Organization criteria and classified into three subtypes: ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The Cox proportional hazards models were used to estimate risk of stroke and its subtypes. During the four-year follow-up, we identified 1614 stroke events (1,156 ischemic, 416 intracerebral hemorrhagic and 42 subarachnoid hemorrhagic). Statistical analyses showed that hazard ratios (HR) (95% Confidence Interval: CI) of serum Non-HDLC level for total and subtypes of stroke were: 1.08 (1.03-1.12) (total), 1.10 (1.05-1.16) (ischemic), 1.03 (0.96-1.10) (intracerebral hemorrhage) and 0.83 (0.66-1.05) (subarachnoid hemorrhage). HR for non-HDLC refers to the increase per each 20 mg/dl. For total and ischemic stroke, the risks were significantly higher in the fourth and fifth quintiles of non-HDLC concentrations compared to the first quintile after adjusting the confounding factors (total stroke: 4(th) quintile HR=1.33 (1.12-1.59); 5(th) quintile HR = 1.36 (1.15-1.62); ischemic stroke: 4(th) quintile HR =1.34 (1.09-1.66); 5(th) quintile HR = 1.53 (1.24-1.88)). Our data suggest that serum non-HDLC level is an independent risk factor for total and ischemic stroke, and that higher serum non-HDLC concentrations are associated with increased risks for total stroke and ischemic stroke, but not for intracerebral and subarachnoid

Serum Cholesterol Levels in College Students: Opportunities for Education and Intervention.

ERIC Educational Resources Information Center

Sparling, Phillip B.; Snow, Teresa K.; Beavers, Bill D.

1999-01-01

Analyzed lipid profiles in 1,088 college students at a university where lipid profiles were available to students in selected health/wellness courses. Mean total cholesterol levels were similar for men and women, but men had significantly lower high-density lipoprotein cholesterol and higher low-density lipoprotein cholesterol than women. About 11…

How cells handle cholesterol.

PubMed

Simons, K; Ikonen, E

2000-12-01

Cholesterol plays an indispensable role in regulating the properties of cell membranes in mammalian cells. Recent advances suggest that cholesterol exerts many of its actions mainly by maintaining sphingolipid rafts in a functional state. How rafts contribute to cholesterol metabolism and transport in the cell is still an open issue. It has long been known that cellular cholesterol levels are precisely controlled by biosynthesis, efflux from cells, and influx of lipoprotein cholesterol into cells. The regulation of cholesterol homeostasis is now receiving a new focus, and this changed perspective may throw light on diseases caused by cholesterol excess, the prime example being atherosclerosis.

Metabolomics reveals the sex-specific effects of the SORT1 low-density lipoprotein cholesterol locus in healthy young adults.

PubMed

Klein, Matthias S; Connors, Kimberly E; Shearer, Jane; Vogel, Hans J; Hittel, Dustin S

2014-11-07

Metabolite profiles of individuals possessing either the cardiovascular risk or protective variants of the low-density lipoprotein cholesterol (LDL-C) associated 1p13.3 locus of the SORT1 gene (rs646776) were analyzed. Serum metabolites and lipids were assessed using LC-MS-based metabolomics in a healthy young population (n = 138: 95 males, 43 females). Although no significant differences were observed in the combined cohort, divergent sex effects were identified. Females carrying the protective allele showed increased phosphatidylcholines, very long chain fatty acids (>C20), and unsaturated fatty acids. Unsaturated fatty acids are considered to be protective against cardiovascular disease. In contrast, males carrying the protective allele exhibited decreased long-chain fatty acids (≤C20) and sphingomyelins, which is similarly considered to decrease cardiovascular disease risk. No significant changes in clinically assessed lipids such as LDL-C, high-density lipoprotein (HDL-C), total cholesterol, or triglycerides were observed in females, whereas only LDL-C was significantly changed in males. This indicates that, apart from reducing LDL-C, other mechanisms may contribute to the protective effect of the SORT1 locus. Thus, the analysis of metabolic biomarkers might reveal early disease development that may be overlooked by relying on standard clinical parameters.

Effect of mipomersen on LDL-cholesterol in patients with severe LDL-hypercholesterolaemia and atherosclerosis treated by lipoprotein apheresis (The MICA-Study).

PubMed

Waldmann, Elisa; Vogt, Anja; Crispin, Alexander; Altenhofer, Julia; Riks, Ina; Parhofer, Klaus G

2017-04-01

In this study, we evaluated the effect of mipomersen in patients with severe LDL-hypercholesterolaemia and atherosclerosis, treated by lipid lowering drugs and regular lipoprotein apheresis. This prospective, randomized, controlled phase II single center trial enrolled 15 patients (9 males, 6 females; 59 ± 9 y, BMI 27 ± 4 kg/m 2 ) with established atherosclerosis, LDL-cholesterol ≥130 mg/dL (3.4 mmol/L) despite maximal possible drug therapy, and fulfilling German criteria for regular lipoprotein apheresis. All patients were on stable lipid lowering drug therapy and regular apheresis for >3 months. Patients randomized to treatment (n = 11) self-injected mipomersen 200 mg sc weekly, at day 4 after apheresis, for 26 weeks. Patients randomized to control (n = 4) continued apheresis without injection. The primary endpoint was the change in pre-apheresis LDL-cholesterol. Of the patients randomized to mipomersen, 3 discontinued the drug early (<12 weeks therapy) for side effects. For these, another 3 were recruited and randomized. Further, 4 patients discontinued mipomersen between 12 and 26 weeks for side effects (moderate to severe injection site reactions n = 3 and elevated liver enzymes n = 1). In those treated for >12 weeks, mipomersen reduced pre-apheresis LDL-cholesterol significantly by 22.6 ± 17.0%, from a baseline of 4.8 ± 1.2 mmol/L to 3.7 ± 0.9 mmol/L, while there was no significant change in the control group (+1.6 ± 9.3%), with the difference between the groups being significant (p=0.02). Mipomersen also decreased pre-apheresis lipoprotein(a) (Lp(a)) concentration from a median baseline of 40.2 mg/dL (32.5,71) by 16% (-19.4,13.6), though without significance (p=0.21). Mipomersen reduces LDL-cholesterol (significantly) and Lp(a) (non-significantly) in patients on maximal lipid-lowering drug therapy and regular apheresis, but is often associated with side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Dapagliflozin in patients with type II diabetes mellitus, with and without elevated triglyceride and reduced high-density lipoprotein cholesterol levels.

PubMed

Bays, Harold E; Sartipy, Peter; Xu, John; Sjöström, Carl David; Underberg, James A

Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor that improves glycemic control in patients with type II diabetes mellitus (T2DM) by reducing renal glucose reabsorption. The aim was to evaluate the lipid effects of dapagliflozin 10 mg or placebo in patients with T2DM with/without baseline elevated triglyceride and reduced high-density lipoprotein (HDL) cholesterol levels. This was a post hoc analysis of 10 phase 3, placebo-controlled studies of dapagliflozin 10 mg (N = 2237) or placebo (N = 2164) administered for 24 weeks in patients with T2DM. Patients with elevated triglyceride (≥150 mg/dL [1.69 mmol/L]) and reduced HDL cholesterol levels (<40 mg/dL [1.04 mmol/L] in men; <50 mg/dL [1.29 mmol/L] in women) were included (group A). The reference group (group B) included patients who did not meet the defined lipid criteria. The effects of dapagliflozin on fasting lipid profiles were generally similar in the 2 lipid groups (ie, groups A and B) and, compared with placebo, were associated with minor increases in non-HDL cholesterol, low-density lipoprotein, and HDL cholesterol levels. The effects on triglyceride levels were inconsistent. The incidence of adverse events (AEs)/serious AEs, and AEs of genital infection, urinary tract infection, volume reduction, renal function, and hypoglycemia were similar in the 2 lipid groups. Patients with T2DM treated with dapagliflozin experienced minor changes in lipid levels; the changes were generally similar in the 2 lipid groups. The clinical significance of these changes in lipids is unclear, especially in view of the positive effects of dapagliflozin on other cardiovascular disease risk factors. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Pleiotropic Effect of Lipoprotein-Apheresis on the Soluble Form of Activated Leukocyte Cell Adhesion Molecule (sALCAM) in Familial Hypercholesterolaemia.

PubMed

von Bauer, Rüdiger; Oikonomou, Dimitrios; Sulaj, Alba; Kopf, Stefan; Fleming, Thomas; Rudofsky, Gottfried; Nawroth, Peter

2018-06-11

Atherosclerosis is an inflammatory disorder in which several converging immune responses modulate and induce lipid accumulation in macrophages. Activated leukocyte cell adhesion molecule (ALCAM) has been described as a structural homologue of HDL-receptor and functions as a pattern recognition receptor (PRR), while its soluble form sALCAM is involved in ALCAM-dependent and -independent immune mechanisms. The aim of this study was to investigate the effect of aggressive removal of low density lipoprotein-cholesterol (LDL-C) and lipoprotein(a) (Lp [a]) by lipoprotein-apheresis (LA) on sALCAM and blood viscosity as well as to evaluate its association with lipoproteins and serum markers of inflammation. © Georg Thieme Verlag KG Stuttgart · New York.

Liver lipase and high-density lipoprotein. Lipoprotein changes after incubation of human serum with rat liver lipase.

PubMed

Groot, P H; Scheek, L M; Jansen, H

1983-05-16

Human sera were incubated with rat liver lipase after inactivation of lecithin:cholesterol acyltransferase, and the changes in serum lipoprotein composition were measured. In the presence of liver lipase serum triacylglycerol and phosphatidylcholine were hydrolyzed. The main changes in the concentrations of these lipids were found in the high-density lipoprotein fraction. Subfractionation of high-density lipoprotein by rate-zonal ultracentrifugation showed a prominent decrease in all constituents of high-density lipoprotein2, a smaller decrease in the 'light' high-density lipoprotein3 and an increase in the 'heavy' high-density lipoprotein3. These data support a concept in which liver lipase is involved in high-density lipoprotein2 phospholipid and triacylglycerol catabolism and suggest that as a result of this action high-density lipoprotein2 is converted into high-density lipoprotein3.

The effects of amoxicillin and vancomycin on parameters reflecting cholesterol metabolism.

PubMed

Baumgartner, S; Reijnders, D; Konings, M C J M; Groen, A K; Lütjohann, D; Goossens, G H; Blaak, E E; Plat, J

2017-10-01

Changes in the microbiota composition have been implicated in the development of obesity and type 2 diabetes. However, not much is known on the involvement of gut microbiota in lipid and cholesterol metabolism. In addition, the gut microbiota might also be a potential source of plasma oxyphytosterol and oxycholesterol concentrations (oxidation products of plant sterols and cholesterol). Therefore, the aim of this study was to modulate the gut microbiota by antibiotic therapy to investigate effects on parameters reflecting cholesterol metabolism and oxyphytosterol concentrations. A randomized, double blind, placebo-controlled trial was performed in which 55 obese, pre-diabetic men received oral amoxicillin (broad-spectrum antibiotic), vancomycin (antibiotic directed against Gram-positive bacteria) or placebo (microcrystalline cellulose) capsules for 7days (1500mg/day). Plasma lipid and lipoprotein, non-cholesterol sterol, bile acid and oxy(phyto)sterol concentrations were determined at baseline and after 1-week intervention. Plasma secondary bile acids correlated negatively with cholestanol (marker for cholesterol absorption, r=-0.367; P<0.05) and positively with lathosterol concentrations (marker for cholesterol synthesis, r=0.430; P<0.05). Fasting plasma secondary bile acid concentrations were reduced after vancomycin treatment as compared to placebo treatment (-0.24±0.22μmol/L vs. -0.08±0.29μmol/L; P<0.01). Vancomycin and amoxicillin treatment did not affect markers for cholesterol metabolism, plasma TAG, total cholesterol, LDL-C or HDL-C concentrations as compared to placebo. In addition, both antibiotic treatments did not affect individual isoforms or total plasma oxyphytosterol or oxycholesterol concentrations. Despite strong correlations between plasma bile acid concentrations and cholesterol metabolism (synthesis and absorption), amoxicillin and vancomycin treatment for 7days did not affect plasma lipid and lipoprotein, plasma non-cholesterol sterol and

Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations.

PubMed

Dubé, Joseph B; Wang, Jian; Cao, Henian; McIntyre, Adam D; Johansen, Christopher T; Hopkins, Scarlett E; Stringer, Randa; Hosseinzadeh, Siyavash; Kennedy, Brooke A; Ban, Matthew R; Young, T Kue; Connelly, Philip W; Dewailly, Eric; Bjerregaard, Peter; Boyer, Bert B; Hegele, Robert A

2015-02-01

Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W. Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P=5.6×10(-49)), which was >3× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34-3.90; P=1.7×10(-17)), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand-binding activity compared with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity. LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications. © 2014 American Heart Association, Inc.

Short-term cooling increases serum triglycerides and small high-density lipoprotein levels in humans.

PubMed

Hoeke, Geerte; Nahon, Kimberly J; Bakker, Leontine E H; Norkauer, Sabine S C; Dinnes, Donna L M; Kockx, Maaike; Lichtenstein, Laeticia; Drettwan, Diana; Reifel-Miller, Anne; Coskun, Tamer; Pagel, Philipp; Romijn, Fred P H T M; Cobbaert, Christa M; Jazet, Ingrid M; Martinez, Laurent O; Kritharides, Leonard; Berbée, Jimmy F P; Boon, Mariëtte R; Rensen, Patrick C N

Cold exposure and β3-adrenergic receptor agonism, which both activate brown adipose tissue, markedly influence lipoprotein metabolism by enhancing lipoprotein lipase-mediated catabolism of triglyceride-rich lipoproteins and increasing plasma high-density lipoprotein (HDL) levels and functionality in mice. However, the effect of short-term cooling on human lipid and lipoprotein metabolism remained largely elusive. The objective was to assess the effect of short-term cooling on the serum lipoprotein profile and HDL functionality in men. Body mass index-matched young, lean men were exposed to a personalized cooling protocol for 2 hours. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition by 1 H-nuclear magnetic resonance. Adenosine triphosphate-binding cassette A1 (ABCA1)-mediated cholesterol efflux capacity of HDL was measured using [ 3 H]cholesterol-loaded ABCA1-transfected Chinese hamster ovary cells. Short-term cooling increased serum levels of free fatty acids, triglycerides, and cholesterol. Cooling increased the concentration of large very low-density lipoprotein (VLDL) particles accompanied by increased mean size of VLDL particles. In addition, cooling enhanced the concentration of small LDL and small HDL particles as well as the cholesterol levels within these particles. The increase in small HDL was accompanied by increased ABCA1-dependent cholesterol efflux in vitro. Our data show that short-term cooling increases the concentration of large VLDL particles and increases the generation of small LDL and HDL particles. We interpret that cooling increases VLDL production and turnover, which results in formation of surface remnants that form small HDL particles that attract cellular cholesterol. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Dietary cholesterol and plasma lipoprotein profiles: Randomized controlled trials

USDA-ARS?s Scientific Manuscript database

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....

Lipoproteins during the estrous cycle in swine.

PubMed

Liu, Ying; Rector, R Scott; Thomas, Tom R; Taylor, Julia A; Holiman, Denise A; Henderson, Kyle K; Welshons, Wade V; Sturek, Michael S

2004-02-01

The purpose of this study was to examine lipoprotein values at high versus low 17beta-estradiol (E2) concentrations in Yucatan miniature swine. Estrous cycles were measured by heat checking the female on a daily basis using a boar. All swine were fed a 1,050-g low-fat, standard chow diet (8% kcal from fat) once per day. Fasted (24 hours) blood samples were collected during low (early luteal, day 5) and high (late follicular, day 18) E2 concentrations to determine differences in concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C), high-density lipoprotein cholesterol (HDL-C), and subfractions. Concentrations of E2 differed significantly from day 5 (3.5 +/- 0.7 pg/mL) to day 18 (14.2 +/- 1.8 pg/mL) of the estrous cycle. Except for HDL(3)-C, all lipoprotein parameters examined were significantly elevated during high E2 versus low E2. TC/HDL-C and LDL-C/HDL-C ratios were significantly lower during the high E2 phase. These results suggest that lipoprotein concentrations fluctuate during the estrous cycle of swine, with high E2 concentrations associated with elevated lipoprotein concentrations.

The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prindiville, John S., E-mail: jprin041@uottawa.ca; Mennigen, Jan A.; Zamora, Jake M.

2011-03-15

Gemfibrozil (GEM) is a fibrate drug consistently found in effluents from sewage treatment plants. This study characterizes the pharmacological effects of GEM on the plasma lipoproteins of rainbow trout (Oncorhynchus mykiss). Our goals were to quantify the impact of the drug on: 1) lipid constituents of lipoproteins (phospholipids (PL), triacylglycerol (TAG), and cholesterol), 2) lipoprotein classes (high, low and very low density lipoproteins), and 3) fatty acid composition of lipoproteins. Potential mechanisms of GEM action were investigated by measuring lipoprotein lipase activity (LPL) and the hepatic gene expression of LPL and of the peroxisome proliferator-activated receptor (PPAR) {alpha}, {beta}, andmore » {gamma} isoforms. GEM treatment resulted in decreased plasma lipoprotein levels (- 29%) and a reduced size of all lipoprotein classes (lower PL:TAG ratios). However, the increase in HDL-cholesterol elicited by GEM in humans failed to be observed in trout. Therefore, HDL-cholesterol cannot be used to assess the impact of the drug on fish. GEM also modified lipoprotein composition by reducing the abundance of long-chain n-3 fatty acids, thereby potentially reducing the nutritional quality of exposed fish. The relative gene expression of LPL was increased, but the activity of the enzyme was not, and we found no evidence for the activation of PPAR pathways. The depressing effects of GEM on fish lipoproteins demonstrated here may be a concern in view of the widespread presence of fibrates in aquatic environments. Work is needed to test whether exposure to environmental concentrations of these drugs jeopardizes the capacity of fish for reproduction, temperature acclimation or migratory behaviors.« less

[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.

Small dense low density lipoprotein-cholesterol and cholesterol ratios to predict arterial stiffness progression in normotensive subjects over a 5-year period.

PubMed

Li, Gang; Wu, Hui-Kun; Wu, Xiao-Wei; Cao, Zhe; Tu, Yuan-Chao; Ma, Yi; Wang, Wei-Qing; Cheng, Jian; Zhou, Zi-Hua

2018-02-12

Small dense low density lipoprotein-cholesterol (sdLDL-C), cholesterol ratios and carotid-femoral pulse wave velocity (cf-PWV) impart risk for all-cause morbidity and mortality independently of conventional cardiovascular disease (CVD) risk factors. This study was designed to identify feasible indicators for predicting arterial stiffness progression. We followed up 816 normotensive participants without diabetes or CVD for nearly 5.0 years. Cholesterol parameters, ratios and other clinical and laboratory data were collected at baseline. cf-PWV were measured at baseline and the end of follow-up. PWV progression subjects had higher levels of PWV parameters, sdLDL-C and TG/HDL-C ratio. sdLDL-C and TG/HDL-C were significantly correlated with all PWV parameters. Multiple regression models showed that sdLDL-C was closely associated with follow-up PWV (β = 0.222, p < 0.001) and △PWV (β = 0.275, p < 0.001). TG/HDL-C was only one cholesterol ratios that associated with all PWV parameters. sdLDL-C (OR = 2.070, 95%CI: 1.162 to 3.688, p = 0.014) and TG/HDL-C (OR = 1.355, 95%CI: 1.136 to 1.617, p = 0.001) could significantly determine the progression of PWV after correction for covariates. High sd-LDL-C quantiles subjects were more likely to develop arterial stiffness progression than low quantiles (Tertiles 3 vs Tertiles1, RR = 2.867, 95%CI: 1.106 to 7.434, p = 0.03). We founded that sdLDL-C and TG/HDL-C ratio can independently predict arterial stiffness progression in normotensive subjects, and high level sdLDL-C and TG/HDL-C ratio were associated with a higher risk of arterial stiffness.

Higher serum cholesterol is associated with intensified age-related neural network decoupling and cognitive decline in early- to mid-life.

PubMed

Spielberg, Jeffrey M; Sadeh, Naomi; Leritz, Elizabeth C; McGlinchey, Regina E; Milberg, William P; Hayes, Jasmeet P; Salat, David H

2017-06-01

Mounting evidence indicates that serum cholesterol and other risk factors for cardiovascular disease intensify normative trajectories of age-related cognitive decline. However, the neural mechanisms by which this occurs remain largely unknown. To understand the impact of cholesterol on brain networks, we applied graph theory to resting-state fMRI in a large sample of early- to mid-life Veterans (N = 206, Mean age  = 32). A network emerged (centered on the banks of the superior temporal sulcus) that evidenced age-related decoupling (i.e., decreased network connectivity with age), but only in participants with clinically-elevated total cholesterol (≥180 mg/dL). Crucially, decoupling in this network corresponded to greater day-to-day disability and mediated age-related declines in psychomotor speed. Finally, examination of network organization revealed a pattern of age-related dedifferentiation for the banks of the superior temporal sulcus, again present only with higher cholesterol. More specifically, age was related to decreasing within-module communication (indexed by Within-Module Degree Z-Score) and increasing between-module communication (indexed by Participation Coefficient), but only in participants with clinically-elevated cholesterol. Follow-up analyses indicated that all findings were driven by low-density lipoprotein (LDL) levels, rather than high-density lipoprotein (HDL) or triglycerides, which is interesting as LDL levels have been linked to increased risk for cardiovascular disease, whereas HDL levels appear inversely related to such disease. These findings provide novel insight into the deleterious effects of cholesterol on brain health and suggest that cholesterol accelerates the impact of age on neural trajectories by disrupting connectivity in circuits implicated in integrative processes and behavioral control. Hum Brain Mapp 38:3249-3261, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s.

PubMed

Kuksis, Arnis; Pruzanski, Waldemar

2008-10-01

We have previously reported preferential release of polyunsaturated FAs during hydrolysis of lipoprotein phosphatidylcholine (PtdCho) by group X secretory phospholipase A2 (sPLA2) and preferential release of oligounsaturated FAs during hydrolysis of lipoprotein PtdCho by group V sPLA2, but the mechanism of this selectivity has remained unknown. We now show that the rate and specificity of hydrolysis are affected by relative increases in endogenous SM and free cholesterol (FC) during the lipase digestion. The highest preference for arachidonate release from LDL and HDL by group X sPLA2 was observed for residual SM/PtdCho molar ratio of 1.2 and 0.4, compared with the respective starting ratios of 0.4 and 0.2, as measured by liquid chromatography/electrospray ionization-mass spectrometry. Group V sPLA2 showed preferential release of linoleate from LDL and HDL at SM/PtdCho ratio 1.5 and 0.6, respectively. We have attributed the change in FA specificity to segregation of molecular species of PtdCho and of sPLA2s between disordered and ordered SM/FC/PtdCho lipid phases. The increases in SM and FC during digestion with group IIA sPLA2 were more limited, and a preferential hydrolysis of any FAs was not observed. The significance of SM and FC SM and FC accumulation during sPLA2 hydrolysis of lipoprotein PtdCho has been previously overlooked.

Interaction between the APOC3 gene promoter polymorphisms, saturated fat intake and plasma lipoproteins.

PubMed

Brown, Sherine; Ordovás, José M; Campos, Hannia

2003-10-01

To test the hypothesis that APOC3 gene polymorphisms modulate the effect of saturated fat (SAT) intake on plasma lipoproteins and LDL size. We studied 336 randomly selected residents from Costa Rica. APOC3 polymorphisms were genotyped in the promoter region (T-455C, T-625del) and the C3238G 3' untranslated region (UTR). Dietary intake was assessed by a validated food-frequency questionnaire (FFQ) and median saturated fat intake (11%) was used to define low and high exposure to saturated fat. Allele frequencies were 0.49, 0.51 and 0.19 for the APOC3-455C, -625de1, and APOC3 3238G alleles, respectively. Significant gene-diet interactions were found for total (P<0.0004) and LDL cholesterol (P<0.01). In homozygotes for the APOC3-455T-625T alleles, saturated fat intake was associated with a 13% increase in total cholesterol (P<0.001) and a 20% increase in LDL cholesterol (P<0.001). In contrast, no association between plasma lipoproteins and saturated fat intake was found among carriers of the APOC3-455C-625del allele. The APOC3 3238G UTR allele did not modify the observed association. Compared to a diet high in saturated fat, a habitually low saturated fat diet is associated with a beneficial lipoprotein profile only among homozygotes of the APOC3 promoter 455T-625T polymorphism.

Molecular pathways in the transformation of model discoidal lipoprotein complexes induced by lecithin:cholesterol acyltransferase.

PubMed

Nichols, A V; Blanche, P J; Gong, E L; Shore, V G; Forte, T M

1985-05-17

Incubation (24 h, 37 degrees C) of discoidal complexes of phosphatidylcholine and apolipoprotein A-I (molar ratio 95 +/- 10 egg yolk phosphatidylcholine-apolipoprotein A-I; 10.5 X 4.0 nm, long X short dimension; designated, class 3 complexes) with the ultracentrifugal d greater than 1.21 g/ml fraction transformed the discoidal complexes to a small product with apparent mean hydrated and nonhydrated diameter of 7.8 and 6.6 nm, respectively. Formation of the small product was associated with marked reduction in phosphatidylcholine-apolipoprotein AI molar ratio of the complexes (on average from 95:1 to 45:1). Phospholipase A2 activity of lecithin:cholesterol acyltransferase participated in the depletion process, as evidenced by production of unesterified fatty acids. In the presence of the d greater than 1.21 g/ml fraction or partially purified lecithin:cholesterol acyltransferase and a source of unesterified cholesterol, the small product could be transformed to a core-containing (cholesteryl ester) round product with a hydrated and nonhydrated diameter of 8.6 and 7.5 nm, respectively. By means of cross-linking with dimethylsuberimidate, the protein moiety of the small product was shown to contain primarily two apolipoprotein A-I molecules per particle, while the large product contained three apolipoprotein A-I molecules per particle. The increase in number of apolipoprotein A-I molecules per particle during transformation of the small to the large product appeared to result from fusion of the small particles during core build-up and release of excess apolipoprotein A-I from the fusion product. The results obtained with the model complexes were consistent for the most part with recent observations (Chen, C., Applegate, K., King, W.C., Glomset, J.A., Norum, K.R. and Gjone, E. (1984) J. Lipid Res. 25, 269-282) on the transformation, by lecithin:cholesterol acyltransferase, of the small spherical high-density lipoproteins of patients with familial lecithin:cholesterol

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,…

Linkage study of the low-density lipoprotein-receptor gene and cholesterol levels in an Afrikaner family. Quantitative genetics and identification of a minor founder effect.

PubMed

Brink, P A; Brink, L T; Torrington, M; Bester, A J

1990-03-17

Overlap of clinical and biochemical characteristics between hypercholesterolaemia in members of the general population and familial hypercholesterolaemic (FH) individuals may lead to misdiagnosis. Quantitative analysis of family data may circumvent this problem. A way of looking for an association between plasma cholesterol levels and restriction fragment length polymorphism markers (RFLP) on the low-density lipoprotein (LDL) receptor gene by using reference cholesterol distributions was explored. Linkage, with a logarithm of the odds (LOD) score of 6.8 at theta 0, was detected between cholesterol levels and the LDL receptor in an extended Afrikaner family. Two RFLP-haplotypes, one previously found in a majority of Afrikaner FH homozygotes, and a second, Stu I-, BstE II+, Pvu II+, Nco I+, were associated with high cholesterol levels in this pedigree.

Beneficial effects of coconut water feeding on lipid metabolism in cholesterol-fed rats.

PubMed

Sandhya, V G; Rajamohan, T

2006-01-01

The purpose of this study was to determine the effect of coconut water feeding in cholesterol-fed rats. Male albino rats were fed tender coconut water and mature coconut water at a dose level of 4 mL/100 g of body weight. Cholesterol feeding caused a marked increase in total cholesterol, very low-density lipoprotein (VLDL) + low-density lipoprotein (LDL) cholesterol, and triglycerides in serum. Administration of coconut water counteracts the increase in total cholesterol, VLDL + LDL cholesterol, and triglycerides, while high-density lipoprotein cholesterol was higher. Lipid levels in the tissues viz. liver, heart, kidney, and aorta were markedly decreased in cholesterol-fed rats supplemented with coconut water. Feeding coconut water resulted in increased activities of 3-hydroxy-3-methylglutaryl-CoA reductase in liver, lipoprotein lipase in heart and adipose tissue, and plasma lecithin:cholesterol acyl transferase, while lipogenic enzymes showed decreased activities. An increased rate of cholesterol conversion to bile acid and an increased excretion of bile acids and neutral sterols were observed in rats fed coconut water. Histopathological studies of liver and aorta revealed much less fatty accumulation in these tissues in cholesterol-fed rats supplemented with coconut water. Feeding coconut water resulted in increased plasma L-arginine content, urinary nitrite level, and nitric oxide synthase activity. These results indicate that both tender and mature coconut water has beneficial effects on serum and tissue lipid parameters in rats fed cholesterol-containing diet.

Genetics of Lipid and Lipoprotein Disorders and Traits.

PubMed

Dron, Jacqueline S; Hegele, Robert A

2016-01-01

Plasma lipids, namely cholesterol and triglyceride, and lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein, serve numerous physiological roles. Perturbed levels of these traits underlie monogenic dyslipidemias, a diverse group of multisystem disorders. We are on the verge of having a relatively complete picture of the human dyslipidemias and their components. Recent advances in genetics of plasma lipids and lipoproteins include the following: (1) expanding the range of genes causing monogenic dyslipidemias, particularly elevated LDL cholesterol; (2) appreciating the role of polygenic effects in such traits as familial hypercholesterolemia and combined hyperlipidemia; (3) accumulating a list of common variants that determine plasma lipids and lipoproteins; (4) applying exome sequencing to identify collections of rare variants determining plasma lipids and lipoproteins that via Mendelian randomization have also implicated gene products such as NPC1L1 , APOC3 , LDLR , APOA5 , and ANGPTL4 as causal for atherosclerotic cardiovascular disease; and (5) using naturally occurring genetic variation to identify new drug targets, including inhibitors of apolipoprotein (apo) C-III, apo(a), ANGPTL3, and ANGPTL4. Here, we compile this disparate range of data linking human genetic variation to plasma lipids and lipoproteins, providing a "one stop shop" for the interested reader.

Impact of oxLDL on Cholesterol-Rich Membrane Rafts

PubMed Central

Levitan, Irena; Shentu, Tzu-Pin

2011-01-01

Numerous studies have demonstrated that cholesterol-rich membrane rafts play critical roles in multiple cellular functions. However, the impact of the lipoproteins on the structure, integrity and cholesterol composition of these domains is not well understood. This paper focuses on oxidized low-density lipoproteins (oxLDLs) that are strongly implicated in the development of the cardiovascular disease and whose impact on membrane cholesterol and on membrane rafts has been highly controversial. More specifically, we discuss three major criteria for the impact of oxLDL on membrane rafts: distribution of different membrane raft markers, changes in membrane cholesterol composition, and changes in lipid packing of different membrane domains. We also propose a model to reconcile the controversy regarding the relationship between oxLDL, membrane cholesterol, and the integrity of cholesterol-rich membrane domains. PMID:21490811

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

The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

USDA-ARS?s Scientific Manuscript database

Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers.

PubMed

Pencek, R; Marmon, T; Roth, J D; Liberman, A; Hooshmand-Rad, R; Young, M A

2016-09-01

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. © 2016 John Wiley & Sons Ltd.

Modulation of Cholesterol-Related Gene Expression by Dietary Fiber Fractions from Edible Mushrooms.

PubMed

Caz, Víctor; Gil-Ramírez, Alicia; Largo, Carlota; Tabernero, María; Santamaría, Mónica; Martín-Hernández, Roberto; Marín, Francisco R; Reglero, Guillermo; Soler-Rivas, Cristina

2015-08-26

Mushrooms are a source of dietary fiber (DF) with a cholesterol-lowering effect. However, their underlying mechanisms are poorly understood. The effect of DF-enriched fractions from three mushrooms species on cholesterol-related expression was studied in vitro. The Pleurotus ostreatus DF fraction (PDF) was used in mice models to assess its potential palliative or preventive effect against hypercholesterolemia. PDF induced a transcriptional response in Caco-2 cells, suggesting a possible cholesterol-lowering effect. In the palliative setting, PDF reduced hepatic triglyceride likely because Dgat1 was downregulated. However, cholesterol-related biochemical data showed no changes and no relation with the observed transcriptional modulation. In the preventive setting, PDF modulated cholesterol-related genes expression in a manner similar to that of simvastatin and ezetimibe in the liver, although no changes in plasma and liver biochemical data were induced. Therefore, PDF may be useful reducing hepatic triglyceride accumulation. Because it induced a molecular response similar to hypocholesterolemic drugs in liver, further dose-dependent studies should be carried out.

Effect of maximal oxygen uptake and different forms of physical training on serum lipoproteins.

PubMed

Schnabel, A; Kindermann, W

1982-01-01

260 well trained male sportsmen between 17 and 30 years of age participating in a variety of events were examined for total serum cholesterol and lipoprotein cholesterol and compared with 37 moderately active leisure-time sportsmen and 20 sedentary controls of similar ages and sex. Lipoprotein cholesterol distribution was determined by quantitative electrophoresis. Mean HDL-cholesterol increased progressively from the mean of the sedentary control to the mean of the long-distance runners, indicating a graded effect of physical activity on HDL-cholesterol. In all sporting groups mean LDL-cholesterol tended to be lower than in the controls, no association between LDL-cholesterol and form of training being apparent. Except for the long-distance runners, all sporting groups tended to be lower in total cholesterol than the controls. The HDL-/total cholesterol and LDL/HDL ratios yielded a better discrimination between the physically active and inactive than the HDL-cholesterol alone. Significant positive correlations with maximal oxygen uptake and roentgenologically determined heart volume were found for HDL-cholesterol and HDL-/total cholesterol, and negative ones for LDL/HDL. Differences in the regressions among subsets made up of sporting groups under different physical demands suggest a positive relationship between lipoprotein distribution and the magnitude of the trained muscle mass.

Consumption of a liquid high-fat meal increases triglycerides but decreases high-density lipoprotein cholesterol in abdominally obese subjects with high postprandial insulin resistance.

PubMed

Wang, Feng; Lu, Huixia; Liu, Fukang; Cai, Huizhen; Xia, Hui; Guo, Fei; Xie, Yulan; Huang, Guiling; Miao, Miao; Shu, Guofang; Sun, Guiju

2017-07-01

Abdominal obesity is associated with an increased risk of insulin resistance, which may be a potential contributor to dyslipidemia. However, the relationship between postprandial insulin resistance and lipid metabolism in abdominally obese subjects remains unknown. We hypothesized that postprandial dyslipidemia would be exaggerated in abdominally obese subjects with high postprandial insulin resistance. To test this hypothesis, serum glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B were measured at baseline and postprandial state at 0.5, 1, 2, 4, 6, and 8 hours after a liquid high-fat meal in non-abdominally obese controls (n=44) and abdominally obese subjects with low (AO-LPIR, n=40), middle (n=40), and high postprandial insulin resistance (AO-HPIR, n=40) based on the tertiles ratio of the insulin to glucose areas under the curve (AUC). Their serum adipokines were tested at baseline only. Fasting serum leptin was higher (P<.05) in AO-HPIR than that in AO-LPIR and controls. Postprandial triglycerides AUC was higher (P<.05), whereas high-density lipoprotein cholesterol AUC was lower (P<.05), in AO-HPIR than those in AO-LPIR and controls. Postprandial AUCs for total cholesterol and apolipoprotein B were similar in abdominally obese subjects with different degrees of postprandial insulin resistance and controls. The present study indicated that the higher degree of postprandial insulin resistance, the more adverse lipid profiles in abdominally obese subjects, which provides insight into opportunity for screening in health. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigation of variants identified in caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in Mexican dyslipidemic study samples.

PubMed

Weissglas-Volkov, Daphna; Aguilar-Salinas, Carlos A; Sinsheimer, Janet S; Riba, Laura; Huertas-Vazquez, Adriana; Ordoñez-Sánchez, Maria L; Rodriguez-Guillen, Rosario; Cantor, Rita M; Tusie-Luna, Teresa; Pajukanta, Päivi

2010-02-01

Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome-wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20 x 10(-3) to 2.6 x 10(-11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6 x 10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans.

Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins.

PubMed

El Harchaoui, Karim; Akdim, Fatima; Stroes, Erik S G; Trip, Mieke D; Kastelein, John J P

2008-01-01

Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.

Metabolic profiles and lipoprotein lipid concentrations in non-obese and obese patients with polycystic ovarian disease.

PubMed

Mahabeer, S; Naidoo, C; Norman, R J; Jialal, I; Reddi, K; Joubert, S M

1990-10-01

Clinical parameters, androgen status and lipoprotein lipid profiles were assessed in 10 non-obese and 10 obese patients with polycystic ovarian disease (PCOD) and reference subjects matched for age, height and weight. Both obese and non-obese women with PCOD had significantly higher androgen levels when compared to the reference groups. When comparison of lipoprotein lipid profiles were made between groups, non-obese women with PCOD had significantly higher total cholesterol, triglycerides and LDL-cholesterol levels than non-obese reference subjects. Obese PCOD women manifested significantly higher total cholesterol, LDL-cholesterol, cholesterol/HDL, and LDL/HDL values than did obese reference subjects. Correlations between serum androgens and lipoprotein lipid concentrations in PCOD and normal women were unhelpful. Both non-obese and obese patients with PCOD had significantly higher systolic and diastolic blood pressures (BPs) than the reference groups. Thus, both non-obese and obese women with PCOD manifest hyperandrogenaemia which may result in a male pattern of lipoprotein lipid concentrations.

Factors affecting high-density lipoprotein cholesterol in HIV-infected patients on nevirapine-based antiretroviral therapy

PubMed Central

Padmapriyadarsini, C.; Ramesh, K.; Sekar, L.; Ramachandran, Geetha; Reddy, Devaraj; Narendran, G.; Sekar, S.; Chandrasekar, C.; Anbarasu, D.; Wanke, Christine; Swaminathan, Soumya

2017-01-01

Background & objectives: Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied. Methods: A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels. Results: Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C. Interpretation & conclusions: High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes. PMID:28948955

Triglyceride to high-density lipoprotein cholesterol ratio and carotid intima-medial thickness in Chinese adolescents with newly diagnosed type 2 diabetes mellitus.

PubMed

Li, Xin; Deng, You-Ping; Yang, Miao; Wu, Yu-Wen; Sun, Su-Xin; Sun, Jia-Zhong

2016-03-01

To investigate the relationship between triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and carotid intima-medial thickness (CIMT) in Chinese youth and adolescents with newly diagnosed type 2 diabetes mellitus (T2DM). Ninety-eight subjects aged 10-24 yr with newly-diagnosed T2DM had general inflammation, anthropometric, laboratory and CIMT data collected, and were divided into three groups based on TG/HDL-C tertiles. There were no significant differences in gender, age, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and carotid arterial diameter (CAD) among the groups based on TG/HDL-C tertiles. Across TG/HDL-C tertiles, there was a significant progressive increase in body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), homeostasis model assessment-estimated insulin resistance (HOMA-IR), TG, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and CIMT (all P < 0.01 or P < 0.05), while HDL-C was decreased significantly across the groups (P < 0.01). In general linear regression model, TG/HDL-C was an independent determinant of CIMT even after adjusting for BMI, SBP, DBP, TG, TC, LDL-C, HDL-C, HbA1c and HOMA-IR. TG/HDL-C ratio, the marker of small dense LDL particles, is an independent determinant of CIMT in Chinese youth and adolescents with newly diagnosed T2DM, and may be a simple and helpful tool in predicting the increased CIMT in such patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Serum lipoprotein changes in dogs with renal disease.

PubMed

Behling-Kelly, E

2014-01-01

People with renal disease develop a dyslipidemia that contributes to progression of renal injury and development of cardiovascular disease. Lipoproteins in dogs with renal disease have not been investigated. Dogs with chronic kidney disease (CKD) have dyslipidemia characterized by increased lower density lipoproteins and decreased high-density lipoproteins (HDLs). The degree of dyslipidemia is positively correlated with severity of disease, as reflected by serum creatinine concentration. Prospective study of client-owned dogs presented to the Cornell University Hospital for Animals: 29 dogs with confirmed CKD, 5 dogs with nephrotic syndrome (NS), and 12 healthy control dogs presented for routine vaccinations, dental cleaning, or owned by students. Lipoprotein electrophoresis was used to quantify relative proportions of the 3 main classes of lipoproteins in canine serum: low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and HDL. Serum cholesterol and creatinine concentrations; urinalysis and urine protein-to-creatinine ratio were measured by standard methods. Dyslipidemia was consistently found in dogs with CKD and NS and was characterized by a decrease in HDL and variable increases in LDL and VLDL. Dogs with NS had a proportionately greater increase in the VLDL fraction, as compared with dogs with CKD. Dyslipidemia similar to that documented in people with renal disease occurs in dogs with CKD, despite serum cholesterol concentrations often being within the reference interval. The contribution of altered lipoproteins to the pathogenesis of renal disease in dogs warrants additional study. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Decreased cholesterol efflux capacity and atherogenic lipid profile in young women with PCOS.

PubMed

Roe, Andrea; Hillman, Jennifer; Butts, Samantha; Smith, Mathew; Rader, Daniel; Playford, Martin; Mehta, Nehal N; Dokras, Anuja

2014-05-01

Women with polycystic ovary syndrome (PCOS) have a high prevalence of cardiovascular disease (CVD) risk factors including dyslipidemia. Lipoproteins are heterogeneous, and measurement of serum lipids provides only the size of the pool and does not predict their function or composition. Recently, high-density lipoprotein cholesterol (HDL-C) function, as determined by cholesterol efflux capacity from macrophages, has been shown to be an independent predictor of subclinical CVD. The aim of the study was to comprehensively evaluate lipoprotein profile including lipid particle size and number and cholesterol efflux capacity in PCOS to better define CVD risk. A case control study was performed at an academic PCOS center. Women with PCOS (n = 124) and geographically matched controls (n = 67) were included in the study. The primary outcome was to measure HDL-C efflux capacity by an ex vivo system involving the incubation of macrophages with apolipoprotein (Apo) B-depleted serum from subjects, and the secondary outcome was to measure lipid particle size and number using nuclear magnetic resonance spectroscopy. Women with PCOS had significantly higher body mass index and blood pressure but similar HDL-C and low-density lipoprotein cholesterol levels compared to controls. The mean ApoA1 levels were lower, and the ApoB/ApoA1 ratio was higher in PCOS subjects compared to controls (P < .01). There were no differences in ApoB levels. Women with PCOS had an 7% decrease in normalized cholesterol efflux capacity compared to controls (P < .003). Cholesterol efflux capacity in PCOS correlated with body mass index, ApoA1, HDL-C, and the presence of metabolic syndrome. In a multivariable regression model, PCOS was significantly associated with diminished cholesterol efflux. PCOS was also associated with an atherogenic profile including an increase in large very low-density lipoprotein particles, very low-density lipoprotein (VLDL) size, and small low-density lipoprotein cholesterol

Decreased Cholesterol Efflux Capacity and Atherogenic Lipid Profile in Young Women With PCOS

PubMed Central

Roe, Andrea; Hillman, Jennifer; Butts, Samantha; Smith, Mathew; Rader, Daniel; Playford, Martin; Mehta, Nehal N.

2014-01-01

Context: Women with polycystic ovary syndrome (PCOS) have a high prevalence of cardiovascular disease (CVD) risk factors including dyslipidemia. Lipoproteins are heterogeneous, and measurement of serum lipids provides only the size of the pool and does not predict their function or composition. Recently, high-density lipoprotein cholesterol (HDL-C) function, as determined by cholesterol efflux capacity from macrophages, has been shown to be an independent predictor of subclinical CVD. Objective: The aim of the study was to comprehensively evaluate lipoprotein profile including lipid particle size and number and cholesterol efflux capacity in PCOS to better define CVD risk. Design and Setting: A case control study was performed at an academic PCOS center. Patients: Women with PCOS (n = 124) and geographically matched controls (n = 67) were included in the study. Main Outcome Measures: The primary outcome was to measure HDL-C efflux capacity by an ex vivo system involving the incubation of macrophages with apolipoprotein (Apo) B-depleted serum from subjects, and the secondary outcome was to measure lipid particle size and number using nuclear magnetic resonance spectroscopy. Results: Women with PCOS had significantly higher body mass index and blood pressure but similar HDL-C and low-density lipoprotein cholesterol levels compared to controls. The mean ApoA1 levels were lower, and the ApoB/ApoA1 ratio was higher in PCOS subjects compared to controls (P < .01). There were no differences in ApoB levels. Women with PCOS had an 7% decrease in normalized cholesterol efflux capacity compared to controls (P < .003). Cholesterol efflux capacity in PCOS correlated with body mass index, ApoA1, HDL-C, and the presence of metabolic syndrome. In a multivariable regression model, PCOS was significantly associated with diminished cholesterol efflux. PCOS was also associated with an atherogenic profile including an increase in large very low-density lipoprotein particles, very low

Lipoprotein profile, lipoprotein-associated phospholipase A2 and cardiovascular risk in hemodialysis patients.

PubMed

Rolla, Roberta; De Mauri, Andreana; Valsesia, Ambra; Vidali, Matteo; Chiarinotti, Doriana; Bellomo, Giorgio

2015-12-01

Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients; the increased risk of cardiovascular disease is due to accelerated atherosclerosis, inflammation and impaired lipoprotein metabolism. We aimed to evaluate lipoprotein-associated phospholipase A2 (Lp-PLA2) and some pro-inflammatory aspects of the lipoprotein profile in dialyzed patients in order to evaluate the relationship with the accelerated atherosclerosis and vascular accidents. In 102 dialysis patients and 40 non-uremic controls, we investigated the lipoprotein plasma profile, high sensitivity C-reactive protein (CRP), ceruloplasmin and serum amyloid A protein (SAA), and followed patients for 1 year to analyze the risk of acute cardiovascular events. Total cholesterol, low-density lipoprotein and high-density lipoprotein plasma levels were significantly lower in uremic patients than controls, whereas CRP, SAA, ceruloplasmin, Lp-PLA2 and their ratio with apolipoprotein A1 were significantly higher. Patients with Lp-PLA2 levels >194 nmol/min/ml had more acute cardiovascular events than patients with lower values. Our results show that in dialysis subjects: (1) low-density lipoproteins show a more atherogenic phenotype than in the general population; (2) high-density lipoproteins are less anti-inflammatory; (3) Lp-PLA2 could potentially be used to evaluate cardiovascular risk.

Liver-specific inhibition of acyl-coenzyme a:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor-/- mice.

PubMed

Bell, Thomas A; Brown, J Mark; Graham, Mark J; Lemonidis, Kristina M; Crooke, Rosanne M; Rudel, Lawrence L

2006-08-01

The purpose of this study was to determine the effects of liver-specific inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) on the development of hypercholesterolemia and atherosclerosis in mice. Apolipoprotein B100-only low-density lipoprotein (LDL) receptor-/- mice were given saline, a nontargeting control antisense oligonucleotide (ASO), or ASOs targeting ACAT2 biweekly for a period spanning 16 weeks. Mice treated with ACAT2 targeting ASOs had liver-specific reduction in ACAT2 mRNA, yet intestinal ACAT2 and cholesterol absorption was left undisturbed. ASO-mediated knockdown of ACAT2 resulted in reduction of total plasma cholesterol, increased levels of plasma triglyceride, and a shift in LDL cholesteryl ester (CE) fatty acid composition from mainly saturated and monounsaturated to polyunsaturated fatty acid enrichment. Furthermore, the liver-specific depletion of ACAT2 resulted in protection against diet-induced hypercholesterolemia and aortic CE deposition. This is the first demonstration that specific pharmacological inhibition of ACAT2, without affecting ACAT1, is atheroprotective. Hepatic ACAT2 plays a critical role in driving the production of atherogenic lipoproteins, and therapeutic interventions, such as the ACAT2-specific ASOs used here, which reduce acyltransferase 2 (ACAT2) function in the liver without affecting ACAT1, may provide clinical benefit for cardiovascular disease prevention.

High triglycerides and low high-density lipoprotein cholesterol lipid profile in rheumatoid arthritis: A potential link among inflammation, oxidative status, and dysfunctional high-density lipoprotein.

PubMed

Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; López-Mejías, Raquel; Alonso-Castro, Sara; Abal, Francisco; Ballina-García, Francisco J; González-Gay, Miguel Á; Suárez, Ana

The interactions between inflammation and lipid profile in rheumatoid arthritis (RA) are poorly understood. The lipid profile study in RA has been biased toward lipoprotein levels, whereas those of triglycerides (TGs) and lipoprotein functionality have been underestimated. Since recent findings suggest a role for TG and TG-rich lipoproteins (TRL) on inflammation, we aimed to evaluate a combined lipid profile characterized by high TG and low high-density lipoprotein cholesterol levels (TG high HDL low ) in RA. Lipid profiles were analyzed in 113 RA patients, 113 healthy controls, and 27 dyslipemic subjects. Levels of inflammatory mediators, paraoxonase-1 (PON1) activity, and total antioxidant capacity were quantified in serum. PON1-rs662 status was evaluated by real-time polymerase chain reaction. The TG high HDL low profile was detected in 29/113 RA patients. Although no differences in prevalence compared with healthy controls or dyslipemic subjects were observed, this profile was associated with increased tumor necrosis factor α (P = .004), monocyte chemotactic protein (P = .004), interferon-gamma-inducible protein-10 (P = .018), and leptin (P < .001) serum levels in RA, where decreased PON1 activity and total antioxidant capacity were found. TG high HDL low prevalence was lower among anti-TNFα-treated patients (P = .004). When RA patients were stratified by PON1-rs662 status, these associations remained in the low-activity genotype (QQ). Finally, a poor clinical response on TNFα blockade was related to an increasing prevalence of the TG high HDL low profile over treatment (P = .021) and higher TRL levels at baseline (P = .042). The TG high HDL low profile is associated with systemic inflammation, decreased PON1 activity, and poor clinical outcome on TNFα blockade in RA, suggesting a role of TRL and HDL dysfunction as the missing link between inflammation and lipid profile. Copyright © 2017 National Lipid Association. Published by Elsevier Inc

Aronia berry polyphenol consumption reduces plasma total and low-density lipoprotein cholesterol in former smokers without lowering biomarkers of inflammation and oxidative stress: a randomized controlled trial.

PubMed

Xie, Liyang; Vance, Terrence; Kim, Bohkyung; Lee, Sang Gil; Caceres, Christian; Wang, Ying; Hubert, Patrice A; Lee, Ji-Young; Chun, Ock K; Bolling, Bradley W

2017-01-01

Former smokers are at increased risk for cardiovascular disease. We hypothesized that dietary aronia polyphenols would reduce biomarkers of cardiovascular disease risk, inflammation, and oxidative stress in former smokers. We also determined the extent these effects were associated with polyphenol bioavailability. A 12-week, randomized, placebo-controlled trial was conducted in 49 healthy adult former smokers (n = 24/placebo, n = 25/aronia) to evaluate if daily consumption of 500 mg aronia extract modulated plasma lipids, blood pressure, biomarkers of inflammation and oxidative stress, and lipid transport genes of peripheral blood mononuclear cells. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C) from baseline, and multivariate correlation analysis was performed to determine if changes in lipids were associated with urinary polyphenol excretion. Aronia consumption reduced fasting plasma total cholesterol by 8% (P = .0140), LDL-C by 11% (P = .0285), and LDL receptor protein in peripheral blood mononuclear cells (P = .0036) at 12 weeks compared with the placebo group. Positive changes in the urinary polyphenol metabolites peonidin-3-O-galactoside, 3-(4-hydroxyphenyl) propionic acid, and unmetabolized anthocyanin cyanidin-3-O-galactoside were associated with lower plasma total cholesterol and LDL-C in the aronia group. Aronia consumption did not change blood pressure or biomarkers of inflammation and oxidative stress. Aronia polyphenols reduced total and LDL-C in former smokers but did not improve biomarkers of oxidative stress and chronic inflammation. The cholesterol-lowering activity of aronia extract was most closely associated with urinary levels of cyanidin-3-O-galactoside and peonidin-3-O-galactoside, its methylated metabolite. This trial was registered at ClinicalTrials.gov as NCT01541826. Copyright © 2016 Elsevier Inc. All rights reserved.

Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation.

PubMed

Syed, Gulam Hussain; Tang, Huihui; Khan, Mohsin; Hassanein, Tarek; Liu, Jingwen; Siddiqui, Aleem

2014-03-01

Lipids play a crucial role in multiple aspects of hepatitis C virus (HCV) life cycle. HCV modulates host lipid metabolism to enrich the intracellular milieu with lipids to facilitate its proliferation. However, very little is known about the influence of HCV on lipid uptake from bloodstream. Low-density lipoprotein receptor (LDLR) is involved in uptake of cholesterol rich low-density lipoprotein (LDL) particles from the bloodstream. The association of HCV particles with lipoproteins implicates their role in HCV entry; however, the precise role of LDLR in HCV entry still remains controversial. Here, we investigate the effect of HCV infection on LDLR expression and the underlying mechanism(s) involved. We demonstrate that HCV stimulates LDLR expression in both HCV-infected Huh7 cells and in liver tissue from chronic hepatitis C patients. Fluorescence activated cell sorting and immunofluorescence analysis revealed enhanced cell surface and total expression of LDLR in HCV-infected cells. Increased LDLR expression resulted in the enhanced uptake of lipoprotein particles by HCV-infected cells. Analysis of LDLR gene promoter identified a pivotal role of sterol-regulatory element binding proteins (SREBPs), in the HCV-mediated stimulation of LDLR transcription. In addition, HCV negatively modulated the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that facilitates LDLR degradation. Ectopic expression of wild-type PCSK9 or gain-of-function PCSK9 mutant negatively affected HCV replication. Overall, our results demonstrate that HCV regulates LDLR expression at transcriptional and posttranslational level via SREBPs and PCSK9 to promote lipid uptake and facilitate viral proliferation. HCV modulates host lipid metabolism to promote enrichment of lipids in intracellular environment, which are essential in multiple aspects of HCV life cycle. However, very little is known about the influence of HCV on lipid uptake from the bloodstream. LDLR is

[Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

PubMed

Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

2014-10-01

The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. © 2014 médecine/sciences – Inserm.

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington's disease.

PubMed

Valenza, M; Marullo, M; Di Paolo, E; Cesana, E; Zuccato, C; Biella, G; Cattaneo, E

2015-04-01

In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyte-neuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD.

Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a Pilot Study

PubMed Central

2012-01-01

Background Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-α (anti-TNFα) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. Methods Twenty-three RA patients starting on anti-TNFα treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. Results Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. Conclusion Anti-TNFα therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function. PMID:22824166

Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).

PubMed

Khera, Amit V; Demler, Olga V; Adelman, Steven J; Collins, Heidi L; Glynn, Robert J; Ridker, Paul M; Rader, Daniel J; Mora, Samia

2017-06-20

Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r = 0.39, 0.48, and 0.39 respectively; P <0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P <0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P =0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P =0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P =0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average

The total cholesterol to high-density lipoprotein cholesterol as a predictor of poor outcomes in a Chinese population with acute ischaemic stroke.

PubMed

Chen, Lifang; Xu, Jianing; Sun, Hao; Wu, Hao; Zhang, Jinsong

2017-11-01

High admission cholesterol has been associated with better outcome after acute ischaemic stroke (AIS), but a paradox not completely illustrated. The purpose of this study was to investigate the effect of the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) on short-term survival after AIS. Consecutive patients admitted in 2013 and 2015 were enrolled in the present study. The logistic regression analysis was conducted to evaluate predictors of 3-month outcomes. The primary endpoint was death. Secondary endpoint was good (modified Rankin Scale score 0-2 or equal to prestrike modified Rankin Scale score) at 3 months. Of 871 patients enrolled in the final analysis, 94 (10.8%) individuals died during 3 months of observation. The serum TC and TC/HDL-C levels at admission were significantly associated with stroke outcomes at 3 months, and the HDL-C level was only correlated with the good outcomes at 3 months. Mortality risk was markedly decreased for patients with high TC/HDL-C ratio (odds ratio: 0.23, 95% confidence interval [CI]: 0.10-0.50 for Q4:Q1; P-trend <.001) after adjustment. The effect of TC/HDL-C ratio on the probability of good outcomes was still obvious (odds ratio: 2.18, 95% CI: 1.40-3.39 for Q4:Q1; P-trend=.029). According to the receiver operating characteristic analyses, the best discriminating factor was a TG/HDL-C ≥3.37 (area under the ROC curve [AUC]=0.643, sensitivity 61.3%, specificity 61.7%) as well as the TC/HDL-C ≥4.09 for good outcomes (AUC: 0.587, sensitivity 63.9%, specificity 79.7%). High TC/HDL-C ratio may be associated with increased short-term survival and better outcomes after AIS. © 2017 Wiley Periodicals, Inc.

Acid sphingomyelinase-deficient macrophages have defective cholesterol trafficking and efflux.

PubMed

Leventhal, A R; Chen, W; Tall, A R; Tabas, I

2001-11-30

Cholesterol efflux from macrophage foam cells, a key step in reverse cholesterol transport, requires trafficking of cholesterol from intracellular sites to the plasma membrane. Sphingomyelin is a cholesterol-binding molecule that transiently exists with cholesterol in endosomes and lysosomes but is rapidly hydrolyzed by lysosomal sphingomyelinase (L-SMase), a product of the acid sphingomyelinase (ASM) gene. We therefore hypothesized that sphingomyelin hydrolysis by L-SMase enables cholesterol efflux by preventing cholesterol sequestration by sphingomyelin. Macrophages from wild-type and ASM knockout mice were incubated with [(3)H]cholesteryl ester-labeled acetyl-LDL and then exposed to apolipoprotein A-I or high density lipoprotein. In both cases, [(3)H]cholesterol efflux was decreased substantially in the ASM knockout macrophages. Similar results were shown for ASM knockout macrophages labeled long-term with [(3)H]cholesterol added directly to medium, but not for those labeled for a short period, suggesting defective efflux from intracellular stores but not from the plasma membrane. Cholesterol trafficking to acyl-coenzyme A:cholesterol acyltransferase (ACAT) was also defective in ASM knockout macrophages. Using filipin to probe cholesterol in macrophages incubated with acetyl-LDL, we found there was modest staining in the plasma membrane of wild-type macrophages but bright, perinuclear fluorescence in ASM knockout macrophages. Last, when wild-type macrophages were incubated with excess sphingomyelin to "saturate" L-SMase, [(3)H]cholesterol efflux was decreased. Thus, sphingomyelin accumulation due to L-SMase deficiency leads to defective cholesterol trafficking and efflux, which we propose is due to sequestration of cholesterol by sphingomyelin and possibly other mechanisms. This model may explain the low plasma high density lipoprotein found in ASM-deficient humans and may implicate L-SMase deficiency and/or sphingomyelin enrichment of lipoproteins as novel

Assembly of high density lipoprotein by the ABCA1/apolipoprotein pathway.

PubMed

Yokoyama, Shinji

2005-06-01

Mammalian somatic cells do not catabolize cholesterol and therefore need to export it for sterol homeostasis at the levels of cells and whole bodies. This mechanism may reduce intracellularly accumulated cholesterol in excess, and thereby would contribute to the prevention or cure of the initial stage of atherosclerotic vascular lesions. HDL is thought to play a main role in this reaction on the basis of epidemiological evidence and in-vitro experimental data. Two independent mechanisms have been identified for this reaction. One is non-specific diffusion-mediated cholesterol 'efflux' from the cell surface, and cholesterol is trapped by various extracellular acceptors including lipoproteins. Extracellular cholesterol esterification on HDL provides a driving force for the net removal of cell cholesterol, and some cellular factors may enhance this reaction. The other mechanism is an apolipoprotein-mediated process to generate HDL by removing cellular phospholipid and cholesterol. This reaction is mediated by a membrane protein ABCA1, and lipid-free or lipid-poor helical apolipoproteins recruit cellular phospholipid and cholesterol to assemble HDL particles. The reaction is composed of two elements: the assembly of HDL particles with phospholipid by apolipoprotein, and cholesterol enrichment in HDL. ABCA1 is essential for the former step, and the latter step requires further intracellular events. ABCA1 is a rate-limiting factor of HDL assembly and is regulated by transcriptional factors and posttranscriptional factors. Posttranscriptional regulation of ABCA1 involves the modulation of its calpain-mediated degradation.

Whole-grain ready-to-eat oat cereal, as part of a dietary program for weight loss, reduces low-density lipoprotein cholesterol in adults with overweight and obesity more than a dietary program including low-fiber control foods.

PubMed

Maki, Kevin C; Beiseigel, Jeannemarie M; Jonnalagadda, Satya S; Gugger, Carolyn K; Reeves, Matthew S; Farmer, Mildred V; Kaden, Valerie N; Rains, Tia M

2010-02-01

Weight loss and consumption of viscous fibers both lower low-density lipoprotein (LDL) cholesterol levels. We evaluated whether or not a whole-grain, ready-to-eat (RTE) oat cereal containing viscous fiber, as part of a dietary program for weight loss, lowers LDL cholesterol levels and improves other cardiovascular disease risk markers more than a dietary program alone. Randomized, parallel-arm, controlled trial. Free-living, overweight and obese adults (N=204, body mass index 25 to 45) with baseline LDL cholesterol levels 130 to 200 mg/dL (3.4 to 5.2 mmol/L) were randomized; 144 were included in the main analysis of participants who completed the trial without significant protocol violations. Two portions per day of whole-grain RTE oat cereal (3 g/day oat b-glucan) or energy-matched low-fiber foods (control), as part of a reduced energy ( approximately 500 kcal/day deficit) dietary program that encouraged limiting consumption of foods high in energy and fat, portion control, and regular physical activity. Fasting lipoprotein levels, waist circumference, triceps skinfold thickness, and body weight were measured at baseline and weeks 4, 8, 10, and 12. LDL cholesterol level was reduced significantly more with whole-grain RTE oat cereal vs control (-8.7+/-1.0 vs -4.3+/-1.1%, P=0.005). Total cholesterol (-5.4+/-0.8 vs -2.9+/-0.9%, P=0.038) and non-high-density lipoprotein-cholesterol (-6.3+/-1.0 vs -3.3+/-1.1%, P=0.046) were also lowered significantly more with whole-grain RTE oat cereal, whereas high-density lipoprotein and triglyceride responses did not differ between groups. Weight loss was not different between groups (-2.2+/-0.3 vs -1.7+/-0.3 kg, P=0.325), but waist circumference decreased more (-3.3+/-0.4 vs -1.9+/-0.4 cm, P=0.012) with whole-grain RTE oat cereal. Larger reductions in LDL, total, and non-high-density lipoprotein cholesterol levels and waist circumference were evident as early as week 4 in the whole-grain RTE oat cereal group. Consumption of a

The Comparison of Gemfibrozil and Lovastatin Therapy in Patients with High LDL and Low HDL Cholesterol Levels

DTIC Science & Technology

1990-08-01

cholesterol with same method as for TC; however, precision of the HDL measurements were (±SD) ±1.5 mg/dl. Triglycerides ( TG ) were...placebo lipid levels (TC and TG levels), lipoprotein cholesterol levels (LDL, VLDL, and HDL cholesterol levels), and the cholesterol ratios between... high density lipoprotein cholesterol in the serum and risk of mortality: evidence of a threshold effect. Br Med J. 1985; 290:1239-43. 7. Gordon

Cholesterol biosynthesis in normocholesterolemic patients after cholesterol removal by plasmapheresis.

PubMed

Feillet, C; Cristol, J P; Michel, F; Kanouni, T; Navarro, R; Navarro, M; Monnier, L; Descomps, B

1997-01-01

Plasmapheresis and low-density lipoprotein (LDL)-apheresis are recognized procedures for the treatment of hyperlipidemia resistant to diet and lipid-lowering drugs and provide information on cholesterol synthesis in hypercholesterolemic patients. However, cholesterol synthesis after acute cholesterol removal from plasma has never been investigated in normocholesterolemic patients. In this study, cholesterol synthesis was evaluated in three normocholesterolemic patients by determination of plasma lathosterol, lathosterol-to-cholesterol ratio, and plasma mevalonic acid. In a short-term kinetic study, samples were collected before and after plasmapheresis and every 6 hours during 24 hours. In the second part of the study, cholesterol synthesis was evaluated daily for 3 days. In normocholesterolemic patients, cholesterol returns to basal levels in 3 days. However, cholesterol removal did not result in a significant increase in lathosterol-to-cholesterol ratio or in plasma mevalonic acid, despite a slight increase in lathosterol. In contrast, when repeated plasma exchanges induced a dramatic hypocholesterolemia (< 1 mmol/liter), an acute but transient stimulation of cholesterol synthesis was observed (lathosterol/cholesterol ratio and MVA, respectively, increase from 8.2 to 22.3 and from 28 nmol/liter to 98 nmol/liter). This study shows that cholesterol synthesis is not stimulated by plasmapheresis in normocholesterolemic patients but is enhanced in dramatic hypocholesterolemic patients (< 1 mmol/liter).

Antioxidative activity of microencapsulated gamma-oryzanol on high cholesterol-fed rats.

PubMed

Suh, Mun-Hee; Yoo, Sang-Ho; Chang, Pahn-Shick; Lee, Hyeon Gyu

2005-12-14

The effectiveness of microencapsulated gamma-oryzanol (M-gamma-OZ) was evaluated as an antioxidant in Sprague-Dawley rats. Lard containing 100 ppm of gamma-OZ (HCD III) or 100 ppm of M-gamma-OZ (HCD IV) was heated in an oven for 7 days, and the heat-treated lard as an ingredient in a high cholesterol diet (HCD) formulation was tested for analyzing in vivo cholesterol and lipid profiles. The HCDs containing fresh lard (HCD I) and heat-treated lard (HCD II) were fed to the rats for 4 weeks as control groups A and B, respectively, in this experiment. The liver thiobarbituric acid reactive substances values of group C (fed with HCD III) and group D (with HCD IV) were significantly lower (p < 0.05) than that of negative control, group B. One of the cholesterol oxidation products, 7-ketocholesterol, was not detected from group D, indicating that microencapsulation preserved antioxidative activity effectively. The levels of serum total cholesterol and lipoproteins, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein were also affected by heat-induced lipid oxidation.The M-gamma-OZ evidently decreased LDL-cholesterol content and increased HDL-cholesterol in blood samples of tested rats. These results suggested that the M-gamma-OZ was not only effective in inhibiting the hypercholesterolemia of serum and liver but also reduced the oxidation degree of lipids and cholesterol. Therefore, this microencapsulation can be a good potential technique to protect the antioxidant activity of gamma-OZ from heat-induced lipid oxidation.

Association between non-high-density lipoprotein cholesterol concentrations and mortality from coronary heart disease among Japanese men and women: the Ibaraki Prefectural Health Study.

PubMed

Noda, Hiroyuki; Iso, Hiroyasu; Irie, Fujiko; Sairenchi, Toshimi; Ohtaka, Emiko; Ohta, Hitoshi

2010-02-01

The aim of this study was to examine whether non-high-density lipoprotein cholesterol (non-HDL-cholesterol) raises the risk of coronary heart disease in a dose-response fashion in a non-obese population with low total cholesterol levels and high HDL-cholesterol levels, such as Japanese. A total of 30,802 men and 60,417 women, aged 40 to 79 years with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993 under the auspices of the Ibaraki Prefectural Health Study. Systematic mortality surveillance through 2003 identified 539 coronary heart disease deaths. The mean values for non-HDL-cholesterol were 140 mg/dL for men and 151 mg/dL for women. The corresponding mean values were 193 mg/dL and 208 mg/dL total cholesterol and 52 mg/dL and 57 mg/dL HDL-cholesterol, respectively. Men with non-HDL-cholesterol > or = 180 mg/dL had a two-fold higher age-adjusted risk of mortality from coronary heart disease than did those with non-HDL-cholesterol <100 mg/dL, whereas no such association was found for women. The multivariable hazard ratio for > or = 180 mg/dL versus <100 mg/dL of non-HDL-cholesterol was 2.22 (95% confidence interval: 1.37 to 3.62) for men and 0.71 (0.37 to 1.34) for women. Higher concentrations of non-HDL-cholesterol were associated with an increased risk of mortality from coronary heart disease for men, but not for women.

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

PubMed Central

Trapani, Laura; Segatto, Marco; Pallottini, Valentina

2013-01-01

Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of

Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

PubMed Central

Holleboom, Adriaan G.; Daniil, Georgios; Fu, Xiaoming; Zhang, Renliang; Hovingh, G. Kees; Schimmel, Alinda W.; Kastelein, John J.P.; Stroes, Erik S.G.; Witztum, Joseph L.; Hutten, Barbara A.; Tsimikas, Sotirios; Hazen, Stanley L.; Chroni, Angeliki; Kuivenhoven, Jan Albert

2013-01-01

Objective Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. Methods and Results In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B–containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose–dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. Conclusion Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL

Pathways by which reconstituted high-density lipoprotein mobilizes free cholesterol from whole body and from macrophages.

PubMed

Cuchel, Marina; Lund-Katz, Sissel; de la Llera-Moya, Margarita; Millar, John S; Chang, David; Fuki, Ilia; Rothblat, George H; Phillips, Michael C; Rader, Daniel J

2010-03-01

Reconstituted high-density lipoprotein (rHDL) is of interest as a potential novel therapy for atherosclerosis because of its ability to promote free cholesterol (FC) mobilization after intravenous administration. We performed studies to identify the underlying molecular mechanisms by which rHDL promote FC mobilization from whole body in vivo and macrophages in vitro. Wild-type (WT), SR-BI knockout (KO), ABCA1 KO, and ABCG1 KO mice received either rHDL or phosphate-buffered saline intravenously. Blood was drawn before and at several time points after injection for apolipoprotein A-I, phosphatidylcholine, and FC measurement. In WT mice, serum FC peaked at 20 minutes and rapidly returned toward baseline levels by 24 hours. Unexpectedly, ABCA1 KO and ABCG1 KO mice did not differ from WT mice regarding the kinetics of FC mobilization. In contrast, in SR-BI KO mice the increase in FC level at 20 minutes was only 10% of that in control mice (P<0.01). Bone marrow-derived macrophages from WT, SR-BI O, ABCA1 KO, and ABCG1 KO mice were incubated in vitro with rHDL and cholesterol efflux was determined. Efflux from SR-BI KO and ABCA1 KO macrophages was not different from WT macrophages. In contrast, efflux from ABCG1 KO macrophages was approximately 50% lower as compared with WT macrophages (P<0.001). The bulk mobilization of FC observed in circulation after rHDL administration is primarily mediated by SR-BI. However, cholesterol mobilization from macrophages to rHDL is primarily mediated by ABCG1.

Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.

PubMed

Martins, Ian J; Berger, Tamar; Sharman, Matthew J; Verdile, Giuseppe; Fuller, Stephanie J; Martins, Ralph N

2009-12-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.

Importance of high-density lipoprotein cholesterol levels in elderly diabetic individuals with type IIb dyslipidemia: A 2-year survey of cardiovascular events.

PubMed

Ina, Koichiro; Hayashi, Toshio; Araki, Atsushi; Kawashima, Seinosuke; Sone, Hirohito; Watanabe, Hiroshi; Ohrui, Takashi; Yokote, Koutaro; Takemoto, Minoru; Kubota, Kiyoshi; Noda, Mitsuhiko; Noto, Hiroshi; Ding, Qun-Fang; Zhang, Jie; Yu, Ze-Yun; Yoon, Byung-Koo; Nomura, Hideki; Kuzuya, Masafumi

2014-10-01

The risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia. The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia. The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged <65 years, 65-74 years and >75 years (n=168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years, and HDL-C and diastolic blood pressure was significantly associated with cardiovascular events in patients aged 65-74 years. Non-HDL-C was not significantly associated with the risk of cardiovascular events. Multiple regression analysis showed that lower HDL-C was significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years and 65-74 years. Lower HDL-C was an important risk factor for cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <75 years. © 2013 Japan Geriatrics Society.

Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.

PubMed Central

Keaney, J F; Gaziano, J M; Xu, A; Frei, B; Curran-Celentano, J; Shwaery, G T; Loscalzo, J; Vita, J A

1993-01-01

Recent evidence suggests that dietary therapy with lipid-soluble antioxidants may be beneficial for patients with atherosclerotic vascular disease but the potential mechanism(s) for these observations remain obscure. Abnormalities in endothelium-dependent control of vascular tone develop early in the course of atherosclerosis and may result from oxidative modification of low density lipoproteins. We examined the role of dietary antioxidants in preserving normal endothelial cell vasodilator function in cholesterol-fed rabbits with particular attention to possible effects on serum lipoproteins, low density lipoprotein oxidation, and atherogenesis. Male New Zealand White rabbits were fed diets containing no additive (controls), 1% cholesterol (cholesterol group), or 1% cholesterol chow supplemented with either beta-carotene (0.6 g/kg of chow) or alpha-tocopherol (1000 international units/kg of chow) for a 28-day period. After dietary therapy, thoracic aortae were harvested for assay of vascular function and for pathologic examination and tissue antioxidant levels. Compared to controls, acetylcholine- and A23187-mediated endothelium-dependent relaxations were significantly impaired in vessels from the cholesterol group (P < 0.001), whereas vessels from animals treated with beta-carotene or alpha-tocopherol demonstrated normal endothelium-dependent arterial relaxation. Preservation of endothelial function was associated with vascular incorporation of alpha-tocopherol and beta-carotene but was unrelated to plasma lipoprotein levels, smooth muscle cell function, or the extent of atherosclerosis. Increased low density lipoprotein resistance to ex vivo copper-mediated oxidation was observed only in the alpha-tocopherol group. Our results suggest that dietary antioxidants may benefit patients with atherosclerosis by preserving endothelial vasodilator function through a mechanism related to vascular tissue antioxidant content and not reflected by assay of low density

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin.

PubMed

Rink, Jonathan S; Yang, Shuo; Cen, Osman; Taxter, Tim; McMahon, Kaylin M; Misener, Sol; Behdad, Amir; Longnecker, Richard; Gordon, Leo I; Thaxton, C Shad

2017-11-06

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

Mechanistic studies of high-density lipoproteins.

PubMed

Kashyap, M L

1998-12-17

There is increasing evidence that high-density lipoprotein (HDL) and its subfractions are protective against atherosclerotic cardiovascular disease. Physical exercise, weight reduction, smoking cessation, diabetes mellitus control, and specific drugs, including niacin, fibrates, and estrogens, are effective methods to increase HDL levels. Niacin is the oldest and most powerful clinical agent for raising HDL levels. Niaspan, an extended-release niacin formulation, is as potent as immediate-release niacin in increasing levels of HDL cholesterol; subfractions HDL2 and HDL3; apolipoprotein A-I, the major protein of HDL, and its cardioprotective subfraction lipoprotein A-I. Recent research from our laboratory suggests a novel mechanism by which niacin inhibits hepatic removal of HDL-apoprotein A-I without interfering with the removal of cholesterol carried by HDL, thus augmenting reverse cholesterol transport. Other mechanistic studies indicate that fibrates and estrogens stimulate the synthesis and production of HDL-apoprotein A-I. Because niacin decreases HDL-apoprotein A-I removal, and fibrates and estrogens increase HDL-apoprotein A-I production, combinations of niacin with these agents may raise HDL levels more than fibrates or estrogens alone.

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

Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.

PubMed

Lotta, Luca A; Sharp, Stephen J; Burgess, Stephen; Perry, John R B; Stewart, Isobel D; Willems, Sara M; Luan, Jian'an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke Mw; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I; Barroso, Inês; O'Rahilly, Stephen; Savage, David B; Sattar, Naveed; Langenberg, Claudia; Scott, Robert A; Wareham, Nicholas J

2016-10-04

Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in

Lipoprotein metabolism in Japanese centenarians: effects of apolipoprotein E polymorphism and nutritional status.

PubMed

Arai, Y; Hirose, N; Nakazawa, S; Yamamura, K; Shimizu, K; Takayama, M; Ebihara, Y; Osono, Y; Homma, S

2001-11-01

To assess the complex interaction of apolipoprotein (apo) E polymorphisms and environmental factors on lipoprotein profile in centenarians. Cross-sectional analysis. Tokyo metropolitan area. Seventy-five centenarians and 73 healthy older volunteers (mean age 63.1 +/- 10.0) living in the Tokyo metropolitan area. Plasma lipids and lipoproteins, cholesteryl ester transfer protein mass, apo E phenotype, body mass index, nutritional indices (serum albumin, prealbumin, transferrin), dietary intake, inflammation markers (C-reactive protein (CRP), interleukin-6 (IL-6)), activities of daily living, and cognitive function. In comparison with older people, the centenarians had low concentrations of total and low-density lipoprotein cholesterol (LDL-C) and a relative predominance of high-density lipoprotein 2 cholesterol. No environmental factor, except the number of apo E epsilon2 alleles, was a significant determinant of LDL-C and apo B, suggesting that the low apo B-containing lipoprotein in centenarians may be attributable to a genetic cause. Centenarians had elevated levels of lipoprotein (a) and decreased high-density lipoprotein cholesterol (HDL-C), which seem to be an unfavorable lipoprotein profile. Lower levels of HDL-C in the centenarians were associated with decreased serum albumin, elevated CRP and IL-6 levels, and cognitive impairment, suggesting that HDL-C could be a sensitive marker for frailty and comorbidity in the oldest old. Low levels of apo B-containing lipoproteins attributable to a genetic cause may be advantageous for longevity. Lipoprotein profiles in centenarians were consistently related to the subjects' nutritional status, inflammation markers, and apo E polymorphisms. The results provide evidence for the importance of maintaining nutritional status in the very old.

Fish protein hydrolysates affect cholesterol metabolism in rats fed non-cholesterol and high-cholesterol diets.

PubMed

Hosomi, Ryota; Fukunaga, Kenji; Arai, Hirofumi; Kanda, Seiji; Nishiyama, Toshimasa; Yoshida, Munehiro

2012-03-01

Fish consumption is well known to provide health benefits in both experimental animals and human subjects. Numerous studies have demonstrated the beneficial effects of various protein hydrolysates on lipid metabolism. In this context, this study examined the effect of fish protein hydrolysates (FPH) on cholesterol metabolism compared with the effect of casein. FPHs were prepared from Alaska pollock meat using papain as a protease. Male Wistar rats were divided into the following four dietary groups of seven rats each: either casein (20%) or FPH (10%) + casein (10%), with or without 0.5% cholesterol and 0.1% sodium cholate. Serum and liver lipid levels, fecal cholesterol and bile acid excretions, and the hepatic expression of genes encoding proteins involved in cholesterol homeostasis were examined. In rats fed the FPH diets compared with casein diets with or without cholesterol and sodium cholate, the indexes of cholesterol metabolism-namely, serum cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels-were significantly lower, whereas fecal cholesterol and bile acid excretions were higher. Rats fed the FPH diets compared with casein with cholesterol exhibited a lower liver cholesterol level via an increased liver cholesterol 7α-hydroxylase (CYP7A1) expression level. This study demonstrates that the intake of FPH has hypocholesterolemic effects through the enhancement of fecal cholesterol and bile acid excretions and CYP7A1 expression levels. Therefore, fish peptides prepared by papain digestion might provide health benefits by decreasing the cholesterol content in the blood, which would contribute to the prevention of circulatory system diseases such as arteriosclerosis.

Mapping Atheroprotective Functions and Related Proteins/Lipoproteins in Size Fractionated Human Plasma.

PubMed

Swertfeger, Debi K; Li, Hailong; Rebholz, Sandra; Zhu, Xiaoting; Shah, Amy S; Davidson, W Sean; Lu, Long J

2017-04-01

HDL has been shown to possess a variety of cardio-protective functions, including removal of excess cholesterol from the periphery, and inhibition of lipoprotein oxidation. It has been proposed that various HDL subparticles exist, each with distinct protein and lipid compositions, which may be responsible for HDL's many functions. We hypothesized that HDL functions will co-migrate with the operational lipoprotein subspecies when separated by gel filtration chromatography. Plasma from 10 healthy male donors was fractionated and the protein composition of the phospholipid containing fractions was analyzed by mass spectrometry (MS). Each fraction was evaluated for its proteomic content as well as its ability to promote cholesterol efflux and protect low density lipoprotein (LDL) from free radical oxidation. For each function, several peaks of activity were identified across the plasma size gradient. Neither cholesterol efflux or LDL antioxidation activity correlated strongly with any single protein across the fractions. However, we identified multiple proteins that had strong correlations (r values >0.7, p < 0.01) with individual peaks of activity. These proteins fell into diverse functional categories, including those traditionally associated with lipid metabolism, as well as alternative complement cascade, innate immunity and clotting cascades and immunoglobulins. Additionally, the phospholipid and cholesterol concentration of the fractions correlated strongly with cholesterol efflux ( r = 0.95 and 0.82 respectively), whereas the total protein content of the fractions correlated best with antioxidant activity across all fractions ( r = 0.746). Furthermore, two previously postulated subspecies (apoA-I, apoA-II and apoC-1; as well as apoA-I, apoC-I and apoJ) were found to have strong correlations with both cholesterol efflux and antioxidation activity. Up till now, very little has been known about how lipoprotein composition mediates functions like cholesterol efflux

Mapping Atheroprotective Functions and Related Proteins/Lipoproteins in Size Fractionated Human Plasma *

PubMed Central

Swertfeger, Debi K.; Li, Hailong; Rebholz, Sandra; Zhu, Xiaoting; Shah, Amy S.; Davidson, W. Sean; Lu, Long J.

2017-01-01

HDL has been shown to possess a variety of cardio-protective functions, including removal of excess cholesterol from the periphery, and inhibition of lipoprotein oxidation. It has been proposed that various HDL subparticles exist, each with distinct protein and lipid compositions, which may be responsible for HDL's many functions. We hypothesized that HDL functions will co-migrate with the operational lipoprotein subspecies when separated by gel filtration chromatography. Plasma from 10 healthy male donors was fractionated and the protein composition of the phospholipid containing fractions was analyzed by mass spectrometry (MS). Each fraction was evaluated for its proteomic content as well as its ability to promote cholesterol efflux and protect low density lipoprotein (LDL) from free radical oxidation. For each function, several peaks of activity were identified across the plasma size gradient. Neither cholesterol efflux or LDL antioxidation activity correlated strongly with any single protein across the fractions. However, we identified multiple proteins that had strong correlations (r values >0.7, p < 0.01) with individual peaks of activity. These proteins fell into diverse functional categories, including those traditionally associated with lipid metabolism, as well as alternative complement cascade, innate immunity and clotting cascades and immunoglobulins. Additionally, the phospholipid and cholesterol concentration of the fractions correlated strongly with cholesterol efflux (r = 0.95 and 0.82 respectively), whereas the total protein content of the fractions correlated best with antioxidant activity across all fractions (r = 0.746). Furthermore, two previously postulated subspecies (apoA-I, apoA-II and apoC-1; as well as apoA-I, apoC-I and apoJ) were found to have strong correlations with both cholesterol efflux and antioxidation activity. Up till now, very little has been known about how lipoprotein composition mediates functions like cholesterol efflux

The Impact of Cardiorespiratory Fitness on Age-Related Lipids and Lipoproteins

PubMed Central

Park, Yong-Moon Mark; Sui, Xuemei; Liu, Junxiu; Zhou, Haiming; Kokkinos, Peter F.; Lavie, Carl J.; Hardin, James W.; Blair, Steven N.

2015-01-01

Background Evidence on the effect of cardiorespiratory fitness (CRF) on age-related longitudinal changes of lipids and lipoproteins is scarce. Objectives This study sought to assess the longitudinal, aging trajectory of lipids and lipoproteins for the life course in adults, and to determine whether CRF modifies the age-associated trajectory of lipids and lipoproteins. Methods Data came from 11,418 men, 20 to 90 years of age, without known high cholesterol, high triglycerides, cardiovascular disease, and cancer at baseline and during follow-up from the Aerobics Center Longitudinal Study. There were 43,821 observations spanning 2 to 25 (mean 3.5) health examinations between 1970 and 2006. CRF was quantified by a maximal treadmill exercise test. Marginal models using generalized estimating equations were applied. Results Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C) presented similar inverted U-shaped quadratic trajectories with aging: gradual increases were noted until the mid-40s to early 50s, with subsequent declines (all p < 0.0001). Compared to men with higher CRF, those with lower CRF developed abnormal values earlier in life: TC (≥200 mg/dl), LDL-C (≥130 mg/dl), non-HDL-C (≥160 mg/dl), and TG/HDL-C ratio (≥3.0). Notably, abnormal values for TC and LDL-C in men with low CRF were observed around 15 years earlier than in those with high CRF. After adjusting for time-varying covariates, a significant interaction was found between age and CRF in each trajectory, indicating that CRF was more strongly associated with the aging trajectories of lipids and lipoproteins in young to middle-aged men than in older men. Conclusions Our investigation reveals a differential trajectory of lipids and lipoproteins with aging according to CRF in healthy men, and suggests that promoting increased CRF levels may help delay the development of dyslipidemia. PMID:25975472

Serum cholesterol and risk of lower urinary tract symptoms progression: Results from the Reduction by Dutasteride of Prostate Cancer Events study.

PubMed

Feng, Tom; Howard, Lauren E; Vidal, Adriana C; Moreira, Daniel M; Castro-Santamaria, Ramiro; Andriole, Gerald L; Freedland, Stephen J

2017-02-01

To determine if cholesterol is a risk factor for the development of lower urinary tract symptoms in asymptomatic men. A post-hoc analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study was carried out in 2323 men with baseline International Prostate Symptom Score <8 and not taking benign prostatic hyperplasia or cholesterol medications. Cox proportion models were used to test the association between cholesterol, high-density lipoprotein, low-density lipoprotein and the cholesterol : high-density lipoprotein ratio with incident lower urinary tract symptoms, defined as first report of medical treatment, surgery or two reports of an International Prostate Symptom Score >14. A total of 253 men (10.9%) developed incident lower urinary tract symptoms. On crude analysis, higher high-density lipoprotein was associated with a decreased lower urinary tract symptoms risk (hazard ratio 0.89, P = 0.024), whereas total cholesterol and low-density lipoprotein showed no association. After multivariable adjustment, the association between high-density lipoprotein and incident lower urinary tract symptoms remained significant (hazard ratio 0.89, P = 0.044), whereas no association was observed for low-density lipoprotein (P = 0.611). There was a trend for higher cholesterol to be linked with higher lower urinary tract symptoms risk, though this was not statistically significant (hazard ratio 1.04, P = 0.054). A higher cholesterol : high-density lipoprotein ratio was associated with increased lower urinary tract symptoms risk on crude (hazard ratio 1.11, P = 0.016) and adjusted models (hazard ratio 1.12, P = 0.012). Among asymptomatic men participating in the REDUCE study, higher cholesterol was associated with increased incident lower urinary tract symptoms risk, though the association was not significant. A higher cholesterol : high-density lipoprotein ratio was associated with increased incident lower urinary tract symptoms, whereas higher high

[Residual risk: The roles of triglycerides and high density lipoproteins].

PubMed

Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

2016-06-01

In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.

Longitudinal Changes in Cholesterol Efflux Capacities in Patients With Coronary Artery Disease Undergoing Lifestyle Modification Therapy.

PubMed

Boyer, Marjorie; Lévesque, Valérie; Poirier, Paul; Marette, André; Mitchell, Patricia L; Mora, Samia; Mathieu, Patrick; Després, Jean-Pierre; Larose, Éric; Arsenault, Benoit J

2018-06-01

Our objective was to identify the determinants of high-density lipoprotein cholesterol efflux capacity (HDL-CEC) changes in patients with coronary artery disease who participated in a lifestyle modification program aimed at increasing physical activity levels and improving diet quality. A total of 86 men with coronary artery disease aged between 35 and 80 years participated in a 1-year lifestyle modification program that aimed to achieve a minimum of 150 minutes of aerobic physical activity weekly and improve diet quality. HDL-CECs were measured before and after the 1-year intervention using 3 H-cholesterol-labeled J774 and HepG2 cells. Visceral, subcutaneous, and cardiac adipose tissue levels were assessed before and after the intervention using magnetic resonance imaging. Lipoprotein particle size and concentrations were measured by proton nuclear magnetic resonance spectroscopy and a complete lipoprotein-lipid profile was obtained. At baseline, the best correlate of HDL-CECs were apolipoprotein AI ( R 2 =0.35, P <0.0001) and high-density lipoprotein cholesterol ( R 2 =0.21, P <0.0001) for J774-HDL-CECs and HepG2-HDL-CECs, respectively. Baseline and longitudinal changes in HDL-CECs were associated with several lipoprotein size and concentration indices, although high-density lipoprotein cholesterol was the best predictor of longitudinal changes in J774-HDL-CECs ( R 2 =0.18, P =0.002) and apolipoprotein AI was found to be the best predictor of longitudinal changes in HepG2 cholesterol efflux capacities ( R 2 =0.21, P =0.002). Results of this study suggest that increases in high-density lipoprotein cholesterol and apolipoprotein AI levels typically observed in patients with coronary artery disease undergoing healthy lifestyle modification therapy may be indicative of higher plasma concentrations of functional high-density lipoprotein particles. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Further LDL cholesterol lowering through targeting PCSK9 for coronary artery disease.

PubMed

Cao, Guoqing; Qian, Yue-Wei; Kowala, Mark C; Konrad, Robert J

2008-12-01

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein convertase family. PCSK9 is synthesized as a zymogen and its prodomain is cleaved by its own catalytic activity. The cleaved prodomain forms a protein complex with the rest of the PCSK9 carboxyl terminus within the endoplasmic reticulum and is secreted. Secreted PCSK9 has been shown to be able to reduce low-density lipoprotein receptor (LDLR) levels in vitro and in vivo. Thus PCSK9 has emerged as an important player modulating LDLR levels and plasma LDL cholesterol. Furthermore, PCSK9 deficiency leads to significantly lowered LDL cholesterol levels in humans and provides dramatic protection against coronary heart disease. We review here the current understanding of PCSK9 and its potential as a therapeutic target through which to reduce LDL cholesterol for prevention and treatment of coronary heart disease.

Effects of short-term niacin treatment on plasma lipoprotein concentrations in African green monkeys (Chlorocebus aethiops).

PubMed

Chauke, Chesa G; Arieff, Zainunisha; Kaur, Mandeep; Seier, Jurgen V

2014-02-01

Niacin is the most effective drug available for raising levels of high-density lipoprotein (HDL) cholesterol. To evaluate its effects on plasma lipid concentrations, the authors administered a low dose of niacin to healthy, adult, female African green monkeys for 3 months. In the treated monkeys, low-density lipoprotein cholesterol concentrations decreased by 43% from baseline, whereas concentrations of HDL cholesterol and apolipoprotein A-I increased by 49% and 34%, respectively. The results suggest that in this primate model, a low dose of niacin can effectively increase concentrations of HDL cholesterol.

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

PubMed

Watts, Gerald F; Chan, Dick C; Dent, Ricardo; Somaratne, Ransi; Wasserman, Scott M; Scott, Rob; Burrows, Sally; R Barrett, P Hugh

2017-01-24

Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures

Serum levels of lipoprotein(a) and homocysteine in patients on hemodialysis who take hydroxymethylglutaryl-CoA reductase inhibitors, vitamin B6, and folic acid.

PubMed

Shojaei, Mir Hatef; Djalali, Mamhmoud; Siassi, Fereydoun; Khatami, Mohammad Reza; Boroumand, Mohammad Ali; Eshragian, Mohammad Reza

2009-07-01

High serum levels of lipoprotein(a) and homocysteine are risk factors of cardiovascular disease which are prevalent in patients on hemodialysis. Controversy exists about the effects of hydroxymethylglutaryl-CoA reductase inhibitors on serum lipoprotein(a) levels in patients on hemodialysis. Also, deficiency of some water soluble vitamins and administration of statins may raise serum levels of homocysteine in these patients. This study was designed to investigate serum levels of lipoprotein(a) and homocysteine in patients on hemodialysis who were taking a statin, vitamin B6, and folic acid. We investigated on 152 patients with maintenance hemodialysis who were taking atorvastatin or lovastatin, vitamin B6, and folic acid for at least 6 months. Their serum levels were obtained to measure lipoprotein(a) and homocysteine levels, as well as triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The mean serum values of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol and triglyceride were significantly less than the maximum reference values (P < .001). The mean serum level of lipoprotein(a) was also less than the reference value (P = .009), but homocysteine level was 33% higher on average than the reference value (P < .001). Our study demonstrated that in our patients on hemodialysis, the mean serum level of homocysteine was about 30% higher than the reference value although they were receiving vitamin B6 and folic acid. Hence, they were still exposed to the risk of cardiovascular disease.

Recovery of Serum Cholesterol Predicts Survival After Left Ventricular Assist Device Implantation

PubMed Central

Vest, Amanda R.; Kennel, Peter J.; Maldonado, Dawn; Young, James B.; Mountis, Maria M.; Naka, Yoshifumi; Colombo, Paolo C.; Mancini, Donna M.; Starling, Randall C.; Schulze, P. Christian

2017-01-01

Background Advanced systolic heart failure is associated with myocardial and systemic metabolic abnormalities, including low levels of total cholesterol and low-density lipoprotein. Low cholesterol and low-density lipoprotein have been associated with greater mortality in heart failure. Implantation of a left ventricular assist device (LVAD) reverses some of the metabolic derangements of advanced heart failure. Methods and Results A cohort was retrospectively assembled from 2 high-volume implantation centers, totaling 295 continuous-flow LVAD recipients with ≥2 cholesterol values available. The cohort was predominantly bridge-to-transplantation (67%), with median age of 59 years and 49% ischemic heart failure cause. Total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride levels all significantly increased after LVAD implantation (median values from implantation to 3 months post implantation 125–150 mg/dL, 67–85 mg/dL, 32–42 mg/dL, and 97–126 mg/dL, respectively). On Cox proportional hazards modeling, patients achieving recovery of total cholesterol levels, defined as a median or greater change from pre implantation to 3 months post-LVAD implantation, had significantly better unadjusted survival (hazard ratio, 0.445; 95% confidence interval, 0.212–0.932) and adjusted survival (hazard ratio, 0.241; 95% confidence interval, 0.092–0.628) than those without cholesterol recovery after LVAD implantation. The continuous variable of total cholesterol at 3 months post implantation and the cholesterol increase from pre implantation to 3 months were also both significantly associated with survival during LVAD support. Conclusions Initiation of continuous-flow LVAD support was associated with significant recovery of all 4 lipid variables. Patients with a greater increase in total cholesterol by 3 months post implantation had superior survival during LVAD support. PMID:27623768

Metabolism of triglyceride-rich lipoproteins and transfer of lipids to high-density lipoproteins (HDL) in vegan and omnivore subjects.

PubMed

Vinagre, J C; Vinagre, C G; Pozzi, F S; Slywitch, E; Maranhão, R C

2013-01-01

Vegan diet excludes all foodstuffs of animal origin and leads to cholesterol lowering and possibly reduction of cardiovascular disease risk. The aim was to investigate whether vegan diet improves the metabolic pathway of triglyceride-rich lipoproteins, consisting in lipoprotein lipolysis and removal from circulation of the resulting remnants and to verify whether the diet alters HDL metabolism by changing lipid transfers to this lipoprotein. 21 vegan and 29 omnivores eutrophic and normolipidemic subjects were intravenously injected triglyceride-rich emulsions labeled with (14)C-cholesterol oleate and (3)H-triolein: fractional clearance rates (FCR, in min(-1)) were calculated from samples collected during 60 min for radioactive counting. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified in supernatant after chemical precipitation of non-HDL fractions and nanoemulsion. Serum LDL cholesterol was lower in vegans than in omnivores (2.1 ± 0.8, 2.7 ± 0.7 mmol/L, respectively, p < 0,05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegans than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal (0.024 ± 0.014, 0.030 ± 0.016, N.S.). Cholesteryl ester transfer to HDL was lower in vegans than in omnivores (2.7 ± 0.6, 3.5 ± 1.5%, p < 0,05). Free-cholesterol, triglyceride and phospholipid transfer were equal, as well as HDL size. Remnant removal from circulation, estimated by cholesteryl oleate FCR was faster in vegans, but the lipolysis process, estimated by triglyceride FCR was equal. Increased removal of atherogenic remnants and diminution of cholesteryl ester transfer may favor atherosclerosis prevention by vegan diet. Copyright © 2011 Elsevier B.V. All rights reserved.

[Lipoproteins as a specific circulatory transport system].

PubMed

Titov, V N

1998-01-01

In accordance with the systemic approach, each circulatory transport system is highly specific and transports an elementary substance from cell to cell in the hydrated medium. In the author's opinion, the lipoprotein system has also a functional specificity and carries the elementary substance fatty acid in the blood stream. A great variety of fatty acids, the individuality of their physicochemical properties, great stereochemic differences of saturated and polyenic fatty acids make their transport virtually impossible. The steric individuality of fatty acids can be reduced if the acids are covalently bonded by a matrix as complex lipids. For formation of complex lipids, nature prefers esterification of fatty acids with alcohols which have a varying hydrophoby, such as glycerol, sphingosine, cholesterol, cetyl alcohol. The steric differences of saturated and polyenic fatty acids form a basis for their being structurized in different lipids. Triacyl glycerides are a transport form of saturated, monounsaturated fatty acids and their transforms and give rise to a crystalline phase. Phospholipids and cholesterol esters are a transport form of mainly polyunsaturated fatty acids in the polar phase in the former case and in the crystalline phase in the latter one. The individual apolipoproteins structure complex lipids into individual lipoprotein particles and transport them in the hydrated medium of blood flow. Saturated fatty acids chiefly transport lipoprotein particles formed by apoB-48- and apoB-100-isoproteins. Polyenic acids transport mainly high-density apoA-1-lipoprotein particles, which makes up a main physiological function of the latter. Cholesterol is nothing more than a matrix; it reesterifies polyenic fatty acids from the polar transport form of phospholipids into the unpolar transport form of cholesterol esters. Cholesterol esterification of polyenic fatty acids may structure complex lipid in the unpolar phase and transport it to the cells via apoB-100

Novel lipoprotein density profiling in healthy dogs of various breeds, healthy miniature schnauzers, and miniature schnauzers with hyperlipidemia

PubMed Central

2013-01-01

Background Despite the importance of abnormalities in lipoprotein metabolism in clinical canine medicine, the fact that most previously used methods for lipoprotein profiling are rather laborious and time-consuming has been a major obstacle to the wide clinical application and use of lipoprotein profiling in this species. The aim of the present study was to assess the feasibility of a continuous lipoprotein density profile (CLPDP) generated within a bismuth sodium ethylenediaminetetraacetic acid (NaBiEDTA) density gradient to characterize and compare the lipoprotein profiles of healthy dogs of various breeds, healthy Miniature Schnauzers, and Miniature Schnauzers with primary hypertriacylglycerolemia. A total of 35 healthy dogs of various breeds with serum triacylglycerol (TAG) and cholesterol concentrations within their respective reference intervals were selected for use as a reference population. Thirty-one Miniature Schnauzers with serum TAG and cholesterol concentrations within their respective reference intervals and 31 Miniature Schnauzers with hypertriacylglyceridemia were also included in the study. Results The results suggest that CLPDP using NaBiEDTA provides unique diagnostic information in addition to measurements of serum TAG and cholesterol concentrations and that it is a useful screening method for dogs with suspected lipoprotein metabolism disorders. Using the detailed and continuous density distribution information provided by the CLPDP, important differences in lipoprotein profiles can be detected even among dogs that have serum TAG and cholesterol concentrations within the reference interval. Miniature Schnauzers with serum TAG and cholesterol concentrations within the reference interval had significantly different lipoprotein profiles than dogs of various other breeds. In addition, it was further established that specific lipoprotein fractions are associated with hypertriacylglyceridemia in Miniature Schnauzers. Conclusions The results of the

Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height

PubMed Central

Williams, Paul T.

2012-01-01

Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3×10−8), HDL-cholesterol (P = 5×10−6), total cholesterol (P = 2.5×10−6), and triglyceride distribution (P = 7.5×10−6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10th population percentile, its effect at the 90th percentile was 4.2-fold greater for BMI, 4.9-fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90th than the 10th percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90th than the 10th percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction). PMID:22235250

Serum lipoprotein (a) concentration in patients with nephrotic syndrome and its clinical implication.

PubMed

Yang, X; Wang, H; Zhu, Z; Deng, A

1998-01-01

Serum lipoprotein(a) [Lp(a)] concentration was determined in 42 patients with primary nephrotic syndrome (NS) and the relationships between Lp (a) and plasma lipids, apolipoproteins, serum creatinine (Scr), albumin, urinary proteins (Upro) were also analyzed. The results showed that: (1) serum Lp(a) concentrations in the patients with NS were higher than those in healthy controls; (2) the levels of serum Lp(a) were correlated positively with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein B (Apo-B), Upros (Upro). It is concluded that the NS patients had the potential risk of suffering from coronary artery disease, glomerular sclerosis and thrombosis. The remission of NS may partially decrease the serum Lp(a) levels. Further studies are needed to explore the prevention and treatment of dislipedemia in patients with NS.

Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.

PubMed

Sprecher, Dennis L; Massien, Christine; Pearce, Greg; Billin, Andrew N; Perlstein, Itay; Willson, Timothy M; Hassall, David G; Ancellin, Nicolas; Patterson, Scott D; Lobe, David C; Johnson, Tony G

2007-02-01

Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)delta expression. In parallel, PPARdelta agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models. Healthy volunteers were allocated placebo (n=6) or PPARdelta agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (-11.5+/-1.6%, P=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (P=0.002). However, LpL expression remained unchanged. This is the first report of a PPARdelta agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.

Can We Eliminate Low-Density Lipoprotein Cholesterol-Related Cardiovascular Events Through More Aggressive Primary Prevention Therapy?

PubMed

Mancini, G B John; Hegele, Robert A

2018-05-01

Intravascular levels of low-density lipoprotein cholesterol (LDL-C) at approximately ≤ 0.6 mmol/L are likely to minimize, and perhaps eliminate, LDL-C-related vascular toxicity while having no effect on essential, intracellular cholesterol homeostatic pathways, according to accumulated knowledge from basic science. Randomized clinical trials, observational reports, and Mendelian randomization trials are also forcing a reconsideration of what "normal" LDL-C means. Recent trials of secondary prevention have substantiated that such levels are safe and associated with a decreased risk of cardiovascular events (CVEs) compared with patients with higher levels of LDL-C. Similarly, treatment to this low range is associated with regression and stabilization of established atherosclerosis. Primary prevention trials also show that low levels of LDL-C are safe and associated with decreased risk of CVEs through cholesterol-lowering in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical outcome trials of familial hypercholesterolemia patients, such patients have very high, lifetime risk of CVE, and registry studies show that LDL-C reduction has nearly normalized their CVE rates. The possibility of familial hypercholesterolemia should be considered if LDL-C is > 4.5 and > 4.0 mmol/L at ages 18-39 years and younger than 18 years, respectively. On the basis of these convergent and internally consistent lines of evidence, in this article we speculate on a translational paradigm aimed at eliminating LDL-C-related CVEs through aggressive primary prevention strategies that are already proven and well accepted in principle. Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Cholesterol depletion modulates detergent resistant fraction of human serotonin(1A) receptors.

PubMed

Sahu, Santosh Kumar; Saxena, Roopali; Chattopadhyay, Amitabha

2012-11-01

Insolubility of membrane components in non-ionic detergents such as Triton X-100 at low temperature is a widely used biochemical criterion to identify, isolate and characterize membrane domains. In this work, we monitored the detergent insolubility of the serotonin(1A) receptor in CHO cell membranes and its modulation by membrane cholesterol. The serotonin(1A) receptor is an important member of the G-protein coupled receptor family. It is implicated in the generation and modulation of various cognitive, behavioral and developmental functions and serves as a drug target. Our results show that a significant fraction (∼28%) of the serotonin(1A) receptor resides in detergent-resistant membranes (DRMs). Interestingly, the fraction of the serotonin(1A) receptor in DRMs exhibits a reduction upon membrane cholesterol depletion. In addition, we show that contents of DRM markers such as flotillin-1, caveolin-1 and GM₁ are altered in DRMs upon cholesterol depletion. These results assume significance since the function of the serotonin(1A) receptor has previously been shown to be affected by membrane lipids, specifically cholesterol. Our results are relevant in the context of membrane organization of the serotonin(1A) receptor in particular, and G-protein coupled receptors in general.

Impact of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio and the Hypertriglyceremic-Waist Phenotype to Predict the Metabolic Syndrome and Insulin Resistance.

PubMed

von Bibra, Helene; Saha, Sarama; Hapfelmeier, Alexander; Müller, Gabriele; Schwarz, Peter E H

2017-07-01

Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations. © Georg Thieme Verlag KG Stuttgart · New York.

Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A₂ mass in type 2 diabetes mellitus: relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity.

PubMed

Constantinides, Alexander; de Vries, Rindert; van Leeuwen, Jeroen J J; Gautier, Thomas; van Pelt, L Joost; Tselepis, Alexandros D; Lagrost, Laurent; Dullaart, Robin P F

2012-10-01

Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels predict incident cardiovascular disease, impacting Lp-PLA(2) as an emerging therapeutic target. We determined Lp-PLA(2) responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationships of changes in Lp-PLA(2) with subclinical inflammation and lipoprotein characteristics. A placebo-controlled cross-over study (three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400mg daily) and their combination) was carried out in 14 male type 2 diabetic patients. Plasma Lp-PLA(2) mass was measured by turbidimetric immunoassay. Plasma Lp-PLA(2) decreased (-21 ± 4%) in response to simvastatin (p<0.05 from baseline and placebo), but was unaffected by bezafibrate (1 ± 5%). The drop in Lp-PLA(2) during combined treatment (-17 ± 3%, p<0.05) was similar compared to that during simvastatin alone. The Lp-PLA(2) changes during the 3 active lipid lowering treatment periods were related positively to baseline levels of high sensitive C-reactive protein, non-HDL cholesterol, triglycerides, the total cholesterol/HDL cholesterol ratio and less LDL electronegativity (p<0.02 to p<0.01), and inversely to baseline Lp-PLA(2) (p<0.01). LpPLA(2) responses correlated inversely with changes in non-HDL cholesterol, triglycerides and the total cholesterol/HDL cholesterol ratio during treatment (p<0.05 to p<0.02). In type 2 diabetes mellitus, plasma Lp-PLA(2) is likely to be lowered by statin treatment only. Enhanced subclinical inflammation and more severe dyslipidemia may predict diminished LpPLA(2) responses during lipid lowering treatment, which in turn appear to be quantitatively dissociated from decreases in apolipoprotein B lipoproteins. Conventional lipid lowering treatment may be insufficient for optimal LpPLA(2) lowering in diabetes mellitus. Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

High-Density Lipoprotein-Targeted Therapy and Apolipoprotein A-I Mimetic Peptides.

PubMed

Uehara, Yoshinari; Chiesa, Giulia; Saku, Keijiro

2015-01-01

Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low-density lipoprotein (LDL) cholesterol and moderately increase that of plasma high-density lipoprotein (HDL) cholesterol. The reverse cholesterol transport pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is optimization of the HDL-cholesterol level and enhanced removal of plasma cholesterol, together with the prevention and mitigation of inflammation related to atherosclerosis. Small-molecule inhibitors of cholesteryl ester transfer protein (CETP) increase the HDL-cholesterol level in subjects with normal or low HDL-cholesterol. However, CETP inhibitors do not seem to reduce the risk of atherosclerotic diseases. HDL therapies using reconstituted HDL, including apolipoprotein (Apo) A-I Milano, ApoA-I mimetics, or full-length ApoA-I, are dramatically effective in animal models. Of those, the ApoA-I-mimetic peptide called FAMP effectively removes cholesterol via the ABCA1 transporter and acts as an antiatherosclerotic agent by enhancing the biological functions of HDL without elevating the HDL-cholesterol level. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases.

Karaya root saponin exerts a hypocholesterolemic response in rats fed a high-cholesterol diet.

PubMed

Afrose, Sadia; Hossain, Md S; Maki, Takaaki; Tsujii, Hirotada

2009-05-01

Different sources of saponins are known to have hypocholesterolemic activity with varying degrees of efficacy. We hypothesize that karaya root saponin would efficiently reduce cholesterol. The aim of this study is to examine the comparative hypocholesterolemic effect of karaya root saponin in rats fed a high-cholesterol diet. Sixty male Wister-Imamichi rats were divided into 5 groups of 12 rats each constituting of the following: control group, soybean saponin-supplemented group, karaya root saponin-supplemented group, quillaja saponin-supplemented group, and tea saponin-supplemented group. Compared with the control diet, both the karaya root- and quillaja saponin-supplemented diets significantly reduced (P < .05) serum cholesterol and atherogenic index. Karaya root saponin significantly increased the serum high-density lipoprotein cholesterol, high-density lipoprotein cholesterol/cholesterol ratio, and fecal cholesterol concentrations (P < .05). The triacylglycerol concentration was significantly reduced only in the quillaja saponin-supplemented rats (P < .05). All the tea, soybean, karaya root, and quillaja saponins significantly reduced low-density lipoprotein cholesterol, and the greatest reduction was observed with karaya root saponin. Highest fecal bile acid concentration was found with quillaja saponin, whereas highest liver bile acid concentration was observed with karaya root saponin-supplemented rats (P < .05). These results collectively suggest that karaya root saponin can efficiently reduce serum cholesterol concentration in rats.

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems.

PubMed

Girotti, Albert W; Korytowski, Witold

2017-12-01

Cholesterol is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular cholesterol resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In low density lipoprotein, cholesterol and phospholipid peroxidation have long been associated with atherogenesis. Among the many intermediates/products of cholesterol oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical-mediated reactions vs. non-radical (e.g., singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of cholesterol and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

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

USDA-ARS?s Scientific Manuscript database

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...

Strategies for vascular disease prevention: the role of lipids and related markers including apolipoproteins, low-density lipoproteins (LDL)-particle size, high sensitivity C-reactive protein (hs-CRP), lipoprotein-associated phospholipase A2 (Lp-PLA₂) and lipoprotein(a) (Lp(a)).

PubMed

Dallmeier, Dhayana; Koenig, Wolfgang

2014-06-01

Considerable progress has been achieved in the treatment of dyslipidemias. However, half of cardiovascular events occur in individuals with average or low cholesterol levels and there is still a considerable residual risk with 70% of patients having an event despite statin treatment. In the era of personalized medicine there is increased interest in the incorporation of individual biomarkers in risk score algorithms in order to improve cardiovascular risk stratification followed by the prompt initiation of preventive measures. Since the 2001 third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment on High Blood Cholesterol in Adults (ATP III) several studies have evaluated the prognostic value of lipid related biomarkers such as non-HDL-cholesterol, apolipoprotein B, apolipoprotein B/apolipoprotein A1 ratio, lipoprotein(a), lipoprotein-associated phospholipase A2, and C-reactive protein. This article tries to summarize the most recent results in this area. Copyright © 2014 Elsevier Ltd. All rights reserved.

Z-Scan Analysis: a New Method to Determine the Oxidative State of Low-Density Lipoprotein and Its Association with Multiple Cardiometabolic Biomarkers

NASA Astrophysics Data System (ADS)

de Freitas, Maria Camila Pruper; Figueiredo Neto, Antonio Martins; Giampaoli, Viviane; da Conceição Quintaneiro Aubin, Elisete; de Araújo Lima Barbosa, Milena Maria; Damasceno, Nágila Raquel Teixeira

2016-04-01

The great atherogenic potential of oxidized low-density lipoprotein has been widely described in the literature. The objective of this study was to investigate whether the state of oxidized low-density lipoprotein in human plasma measured by the Z-scan technique has an association with different cardiometabolic biomarkers. Total cholesterol, high-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I and apolipoprotein B, paraoxonase-1, and glucose were analyzed using standard commercial kits, and low-density lipoprotein cholesterol was estimated using the Friedewald equation. A sandwich enzyme-linked immunosorbent assay was used to detect electronegative low-density lipoprotein. Low-density lipoprotein and high-density lipoprotein sizes were determined by Lipoprint® system. The Z-scan technique was used to measure the non-linear optical response of low-density lipoprotein solution. Principal component analysis and correlations were used respectively to resize the data from the sample and test association between the θ parameter, measured with the Z-scan technique, and the principal component. A total of 63 individuals, from both sexes, with mean age 52 years (±11), being overweight and having high levels of total cholesterol and low levels of high-density lipoprotein cholesterol, were enrolled in this study. A positive correlation between the θ parameter and more anti-atherogenic pattern for cardiometabolic biomarkers together with a negative correlation for an atherogenic pattern was found. Regarding the parameters related with an atherogenic low-density lipoprotein profile, the θ parameter was negatively correlated with a more atherogenic pattern. By using Z-scan measurements, we were able to find an association between oxidized low-density lipoprotein state and multiple cardiometabolic biomarkers in samples from individuals with different cardiovascular risk factors.

Association of Air Pollution Exposures With High-Density Lipoprotein Cholesterol and Particle Number: The Multi-Ethnic Study of Atherosclerosis.

PubMed

Bell, Griffith; Mora, Samia; Greenland, Philip; Tsai, Michael; Gill, Ed; Kaufman, Joel D

2017-05-01

The relationship between air pollution and cardiovascular disease may be explained by changes in high-density lipoprotein (HDL). We examined the cross-sectional relationship between air pollution and both HDL cholesterol and HDL particle number in the MESA Air study (Multi-Ethnic Study of Atherosclerosis Air Pollution). Study participants were 6654 white, black, Hispanic, and Chinese men and women aged 45 to 84 years. We estimated individual residential ambient fine particulate pollution exposure (PM 2.5 ) and black carbon concentrations using a fine-scale likelihood-based spatiotemporal model and cohort-specific monitoring. Exposure periods were averaged to 12 months, 3 months, and 2 weeks prior to examination. HDL cholesterol and HDL particle number were measured in the year 2000 using the cholesterol oxidase method and nuclear magnetic resonance spectroscopy, respectively. We used multivariable linear regression to examine the relationship between air pollution exposure and HDL measures. A 0.7×10 - 6 m - 1 higher exposure to black carbon (a marker of traffic-related pollution) averaged over a 1-year period was significantly associated with a lower HDL cholesterol (-1.68 mg/dL; 95% confidence interval, -2.86 to -0.50) and approached significance with HDL particle number (-0.55 mg/dL; 95% confidence interval, -1.13 to 0.03). In the 3-month averaging time period, a 5 μg/m 3 higher PM 2.5 was associated with lower HDL particle number (-0.64 μmol/L; 95% confidence interval, -1.01 to -0.26), but not HDL cholesterol (-0.05 mg/dL; 95% confidence interval, -0.82 to 0.71). These data are consistent with the hypothesis that exposure to air pollution is adversely associated with measures of HDL. © 2017 American Heart Association, Inc.

Association between Low-density lipoprotein cholesterol and occipital periventricular hyperintensities in a group of Chinese patients: an observational study.

PubMed

Duan, Dazhi; Shen, Lin; Cui, Chun; Shu, Tongsheng; Zheng, Jian

2017-02-27

While occipital periventricular hyperintensities (OPVHs) are among the most common mild white matter hyperintensities, the clinical factors associated with OPVHs remain unclear. In this study, we investigated the role of clinical factors in development of pure OPVHs. This study included 97 patients with OPVHs and 73 healthy controls. Univariate analysis of clinical factors in OPVH patients and controls was followed by binomial logistic regression analysis to identify clinical factors significantly associated with OPVHs. Univariate analysis indicated that age, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein-B (Apo-B) levels differed significantly between the OPVH patients and controls (p < 0.05). Age and gender were correlated with OPVH scores (p < 0.05), while LDL-C, triglycerides, Apo-B and TC were anti-correlated with OPVHs scores (p < 0.05). Multivariate analysis indicated that LDL-C is negatively correlated with OPVHs (p < 0.05), and age is positively correlated with OPVHs (p < 0.001). In summary, LDL-C was negatively and age was positively associated with OPVHs among Chinese patients in a hospital.

The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart.

PubMed

Korolenko, Tatyana A; Tuzikov, Fedor V; Johnston, Thomas P; Tuzikova, Natalia A; Kisarova, Yana A; Zhanaeva, Svetlana Ya; Alexeenko, Tatyana V; Zhukova, Natalia A; Brak, Ivan V; Spiridonov, Victor K; Filjushina, Elena E; Cherkanova, Marina S; Monoszon, Anna A

2012-11-01

The effects of repeated administration of poloxamer 407 (P-407) on lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subfractions, as well as the effect on liver and heart proteases, were studied. Repeated administration of P-407 to male CBA mice resulted in a model of atherosclerosis with increased diastolic blood pressure; there was a drastic increase in total serum cholesterol and especially TG. A novel small-angle X-ray scattering method for the determination of the fractional and subfractional composition of LP-C and LP-TG was used. In chronically P-407-treated mice, P-407 significantly increased atherogenic low-density lipoprotein C (LDL-C) fractions, as well as intermediate-density lipoprotein C (IDL-C), and LDL₁₋₃-C subfractions, and very-low-density lipoprotein-C (VLDL-C) fractions, as well as VLDL₁₋₂-C and VLDL₃₋₅-C subfractions), to a lesser extent, the total anti-atherogenic high-density lipoprotein C (HDL-C) fraction, as well as HDL₂-C and HDL₃-C subfractions. Additionally, we demonstrated an increase in the serum chitotriosidase activity, without significant changes in serum matrix metalloprotease (MMP) activity. Morphological changes observed in P-407-treated mice included atherosclerosis in the heart and storage syndrome in the liver macrophages. P-407 significantly increased the activity of cysteine, aspartate proteases, and MMPs in the heart, and only the activity of cathepsin B and MMPs in the liver of mice. Thus, repeated administration of P-407 to mice induced atherosclerosis secondary to sustained dyslipidemia and formation of foamy macrophages in liver, and also modulated the activity of heart and liver proteases.

Effects of dietary cholesterol supplementation on growth and cholesterol metabolism of rainbow trout (Oncorhynchus mykiss) fed diets with cottonseed meal or rapeseed meal.

PubMed

Deng, Junming; Zhang, Xi; Long, Xiaowen; Tao, Linli; Wang, Zhen; Niu, Guoyi; Kang, Bin

2014-12-01

This study was conducted to evaluate the effects of cholesterol on growth and cholesterol metabolism of rainbow trout (Oncorhynchus mykiss) fed diets with cottonseed meal (CSM) or rapeseed meal (RSM). Four experimental diets were formulated to contain 550 g kg(-1) CSM or 450 g kg(-1) RSM with or without 9 g kg(-1) supplemental cholesterol. Growth rate and feed utilization efficiency of fish fed diets with 450 g kg(-1) RSM were inferior to fish fed diets with 550 g kg(-1) CSM regardless of cholesterol level. Dietary cholesterol supplementation increased the growth rate of fish fed diets with RSM, and growth rate and feed utilization efficiency of fish fed diets with CSM. Similarly, dietary cholesterol supplementation increased the plasma total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triiodothyronine levels, but decreased the plasma triglycerides and cortisol levels of fish fed diets with RSM or CSM. In addition, supplemental cholesterol increased the free cholesterol and TC levels in intestinal contents, but decreased the hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase activity of fish fed diets with RSM or CSM. These results indicate that 9 g kg(-1) cholesterol supplementation seems to improve the growth of rainbow trout fed diets with CSM or RSM, and the growth-promoting action may be related to the alleviation of the negative effects caused by antinutritional factors and/or make up for the deficiency of endogenous cholesterol in rainbow trout.

Serum cholesterol concentrations among Navajo Indians.

PubMed Central

Sugarman, J R; Gilbert, T J; Percy, C A; Peter, D G

1992-01-01

Navajo Indians have been reported by earlier investigators to have low concentrations of serum lipids and a low prevalence of hyperlipidemia, as well as low rates of ischemic heart disease. However, no data on serum lipid concentrations among Navajos have been reported for more than two decades. The authors conducted a study to determine the distribution of concentrations of serum total cholesterol (TC), high density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglyceride among persons 25-74 years old living in a representative community on the Navajo Indian reservation. Data are reported for 255 subjects, 105 men and 150 women, ages 25-74 years. The authors compared these data to those for the general population as determined by the second National Health and Nutrition Examination Survey (NHANES II). TC concentrations among Navajo men were similar to those from NHANES II. TC concentrations among younger Navajo women were similar to those for women younger than 55 years from NHANES II, but were significantly lower among older Navajo women. While 27.6 percent of men ages 25-74 years studied in NHANES II had TC concentrations greater than 240 milligrams per deciliter, 33.8 percent of Navajo men had similarly elevated TC. However, the prevalence of serum TC concentrations greater than 240 milligrams per deciliter among Navajo women (17.5 percent) was about half that among women studied in NHANES II (32.9 percent). A similar pattern was found for low density lipoprotein cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1738814

Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors.

PubMed

Morel, Sophia; Leahy, Jade; Fournier, Maryse; Lamarche, Benoit; Garofalo, Carole; Grimard, Guy; Poulain, Floriane; Delvin, Edgard; Laverdière, Caroline; Krajinovic, Maja; Drouin, Simon; Sinnett, Daniel; Marcil, Valérie; Levy, Emile

2017-05-01

Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL 3 HDL 2 , especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III 1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Methionine deficiency in rats fed soy protein induces hypercholesterolemia and potentiates lipoprotein susceptibility to peroxidation.

PubMed

Moundras, C; Rémésy, C; Levrat, M A; Demigné, C

1995-09-01

A number of studies have provided evidence that plant proteins, especially soy protein, have a cholesterol-lowering effect as compared with casein. However, dietary supply of sulfur amino acids may be deficient when soy protein is present in the diet at a suboptimal level, which could affect lipid metabolism. Accordingly, in rats fed 13% protein diets, soy protein feeding resulted in a cholesterol-increasing effect (+18%), which could be counteracted by methionine supplementation (0.4%). In contrast, soy protein was effective in decreasing plasma triglyceride, as compared with levels in rats fed casein; this triglyceride-lowering effect was entirely abolished by methionine supplementation. The hypercholesterolemic effect of soy protein was characterized by a higher cholesterol content in low-density lipoprotein (LDL) and high-density lipoprotein 1 (HDL1) fractions, together with a marked induction of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase activity and to a lesser extent cholesterol 7 alpha-hydroxylase. There was practically no induction of these enzymes, as compared with levels in rats fed casein diets, when the soy protein diet was supplemented with methionine. Very-low-density lipoprotein (VLDL) plus LDL susceptibility to peroxidation was higher in rats fed soy protein than in casein-fed rats, which could reflect in part the lack of sulfur amino acid availability, since methionine supplementation led to a partial recovery of lipoprotein resistance to peroxidation. These findings suggest that amino acid imbalance could be atherogenic by increasing circulating cholesterol and leading to a higher lipoprotein susceptibility to peroxidation.

Workplace exposure to environmental tobacco smoke and high density lipoprotein cholesterol among nonsmokers.

PubMed

Mizoue, T; Ueda, R; Hino, Y; Yoshimura, T

1999-11-15

There are few epidemiologic studies among adult nonsmokers on the effects of workplace environmental tobacco smoke on high density lipoprotein cholesterol (HDL-C). The authors investigated this relation, using data from health examinations conducted in 1995 on 3,062 Japanese nonsmokers in a total of 27 municipal offices with few smoking restrictions. Multiple regression analysis with adjustments for age, body mass index, alcohol drinking, and sports activities showed that in women, and in men lacking both alcohol consumption and sports activities characteristics, there were inverse linear relations between workplace smoking indices and HDL-C levels. Multivariate logistic regression showed that nonsmoking women in the upper two thirds of offices ranked by smoking intensity had an increased risk of low HDL-C levels (<45 mg), taking those in the lowest third of offices as reference (the medium third: odds ratio = 1.7; 95% confidence interval: 1.2, 2.5; the highest third: odds ratio = 1.6; 95% confidence interval: 1.1, 2.4). The results indicated that workplace environmental tobacco smoke exposure is associated with HDL-C among nonsmokers. However, the lack of data on home exposure limits causal inferences about the effects of workplace exposure.

Red blood cells play a role in reverse cholesterol transport.

PubMed

Hung, Kimberly T; Berisha, Stela Z; Ritchey, Brian M; Santore, Jennifer; Smith, Jonathan D

2012-06-01

Reverse cholesterol transport (RCT) involves the removal of cholesterol from peripheral tissue for excretion in the feces. Here, we determined whether red blood cells (RBCs) can contribute to RCT. We performed a series of studies in apolipoprotein AI-deficient mice where the high-density lipoprotein-mediated pathway of RCT is greatly diminished. RBCs carried a higher fraction of whole blood cholesterol than plasma in apolipoprotein AI-deficient mice, and as least as much of the labeled cholesterol derived from injected foam cells appeared in RBCs compared with plasma. To determine whether RBCs mediate RCT to the fecal compartment, we measured RCT in anemic and control apolipoprotein AI-deficient mice and found that anemia decreased RCT to the feces by over 35% after correcting for fecal mass. Transfusion of [(3)H]cholesterol-labeled RBCs led to robust delivery of the labeled cholesterol to the feces in apolipoprotein AI-deficient hosts. In wild-type mice, the majority of the blood cholesterol mass, as well as [(3)H]cholesterol derived from the injected foam cells, was found in plasma, and anemia did not significantly alter RCT to the feces after correction for fecal mass. The RBC cholesterol pool is dynamic and facilitates RCT of peripheral cholesterol to the feces, particularly in the low high-density lipoprotein state.

Modulation of lipoprotein metabolism by antisense technology: preclinical drug discovery methodology.

PubMed

Crooke, Rosanne M; Graham, Mark J

2013-01-01

Antisense oligonucleotides (ASOs) are a new class of specific therapeutic agents that alter the intermediary metabolism of mRNA, resulting in the suppression of disease-associated gene products. ASOs exert their pharmacological effects after hybridizing, via Watson-Crick base pairing, to a specific target RNA. If appropriately designed, this event results in the recruitment of RNase H, the degradation of targeted mRNA or pre-mRNA, and subsequent inhibition of the synthesis of a specific protein. A key advantage of the technology is the ability to selectively inhibit targets that cannot be modulated by traditional therapeutics such as structural proteins, transcription factors, and, of topical interest, lipoproteins. In this chapter, we will first provide an overview of antisense technology, then more specifically describe the status of lipoprotein-related genes that have been studied using the antisense platform, and finally, outline the general methodology required to design and evaluate the in vitro and in vivo efficacy of those drugs.

Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism.

PubMed

Haymana, Cem; Sonmez, Alper; Aydogdu, Aydogan; Tapan, Serkan; Basaran, Yalcin; Meric, Coskun; Baskoy, Kamil; Dinc, Mustafa; Yazici, Mahmut; Taslipinar, Abdullah; Barcin, Cem; Yilmaz, Mahmut Ilker; Bolu, Erol; Azal, Omer

2017-01-01

Cardiometabolic risk is high in patients with hypogonadism. Visceral adiposity index (VAI) and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio are the practical markers of atherosclerosis and insulin resistance and independent predictors of cardiaovascular risk. To date, no study has evaluated VAI levels and TG/HDL-C ratio in hypogonadism. A total of 112 patients with congenital hypogonadotrophic hypogonadism (CHH) (mean age, 21.7 ± 2.06 years) and 124 healthy subjects (mean age, 21.5 ± 1.27 years) were enrolled. The demographic parameters, VAI, TG/HDL-C ratio, asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured for all participants. The patients had higher total cholesterol (p = 0.04), waist circumference, triglycerides, insulin, and HOMA-IR levels (p = 0.001 for all) than the healthy subjects. VAI and ADMA and TG/HDL-C levels were also higher in patients than in healthy subjects (p < 0.001 for all). VAI was weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04), and total testosterone (r = -0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated weakly with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006), and total testosterone (r = -0.16, p = 0.03) levels. Neither VAI nor TG/HDL-C ratio determined ADMA, HOMA-IR, and hs-CRP levels. The results of this study demonstrate that patients with hypogonadism have elevated VAI and TG/HDL-C ratio. These values are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in predicting cardiometabolic risk in patients with hypogonadism.

Food Ingredients That Inhibit Cholesterol Absorption

PubMed Central

Jesch, Elliot D.; Carr, Timothy P.

2017-01-01

Cholesterol is a vital component of the human body. It stabilizes cell membranes and is the precursor of bile acids, vitamin D and steroid hormones. However, cholesterol accumulation in the bloodstream (hypercholesterolemia) can cause atherosclerotic plaques within artery walls, leading to heart attacks and strokes. The efficiency of cholesterol absorption in the small intestine is of great interest because human and animal studies have linked cholesterol absorption with plasma concentration of total and low density lipoprotein cholesterol. Cholesterol absorption is highly regulated and influenced by particular compounds in the food supply. Therefore, it is desirable to learn more about natural food components that inhibit cholesterol absorption so that food ingredients and dietary supplements can be developed for consumers who wish to manage their plasma cholesterol levels by non-pharmacological means. Food components thus far identified as inhibitors of cholesterol absorption include phytosterols, soluble fibers, phospholipids, and stearic acid. PMID:28702423

Lipoprotein Agarose Gel Electrophoresis. Application in HDL-Cholesterol Methodology.

DTIC Science & Technology

1985-06-01

on determination of high-density lipo- protein cholesterol by precipitation with sodium phosphotungstate- magnesium. Clin Chem 25(4):560 (1979). 6...determinations of cholesterol levels in supernates obtained after addition of various amounts of precipitants , lipo- protein electrophoresis can help to...plotted against the corresponding volumes of sodium phosphotungstate-MgCl2 (NAPT) precipitant added. 10 ’ ’’ ’i - n

Combined training (strength plus aerobic) potentiates a reduction in body fat but only functional training reduced low-density lipoprotein cholesterol in postmenopausal women with a similar training load.

PubMed

Rossi, Fabrício Eduardo; Fortaleza, Ana Claudia S; Neves, Lucas M; Diniz, Tiego A; de Castro, Marcela R; Buonani, Camila; Mota, Jorge; Freitas, Ismael F

2017-06-01

The aim of this study was to compare the effects of combined (CT; strength plus aerobic) and functional training (FT) on the body composition and metabolic profile with a similar training load in postmenopausal women. The participants were divided into three groups: CT (n=20), FT (n=17), and control group (CG, n=15). The trunk FM, fat mass (FM), percentage of FM (FM%), and fat-free mass were estimated by dual-energy X-ray absorptiometry. The metabolic profile, glucose, triacylglycerol, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-c) were assessed. There were main effects of time in trunk fat, FM, and FM% ( P <0.05). There were statistically significant interaction for FM ( P =0.015), FM% ( P =0.017) with lower values for CT group. For LDL-c, there was significant interaction ( P =0.002) with greater values for FT group in relation to CG and CT. Furthermore, when performed the post hoc test on the "mean absolute differences" (Δ), it can observed statistically significant difference between FT, CT, and CG (-13.0±16.5 mg/dL vs. 4.8±18.4 mg/dL vs. 9.2±18.8 mg/dL, P <0.05). In conclusion, when training loads are equivalent CT potentiated a reduction in FM and FM%, however, only FT reduced LDL-c in postmenopausal women.

How Do Elevated Triglycerides and Low HDL-Cholesterol Affect Inflammation and Atherothrombosis?

PubMed Central

Welty, Francine K.

2015-01-01

This review article summarizes recent research into the mechanisms as to how elevated levels of triglyceride (TG) and low levels of high- density- lipoprotein cholesterol (HDL-C) contribute to inflammation and atherosclerosis. Evidence supports the role of TG-rich lipoproteins in signaling mechanisms via apolipoproteins C-III and free fatty acids leading to activation of NFKβ, VCAM-1 and other inflammatory mediators which lead to fatty streak formation and advanced atherosclerosis. Moreover, the cholesterol content in TG-rich lipoproteins has been shown to predict CAD risk better than LDL-C. In addition to reverse cholesterol transport, HDL has many other cardioprotective effects which include regulating immune function. The “functionality” of HDL appears more important than the level of HDL-C. Insulin resistance and central obesity underlie the pathophysiology of elevated TG and low HDL-C in metabolic syndrome and type 2 diabetes. Lifestyle recommendations including exercise and weight loss remain first line therapy in ameliorating insulin resistance and the adverse signaling processes from elevated levels of TG-rich lipoproteins and low HDL-C. PMID:23881582

Effect of honey on serum cholesterol and lipid values.

PubMed

Münstedt, Karsten; Hoffmann, Sven; Hauenschild, Annette; Bülte, Michael; von Georgi, Richard; Hackethal, Andreas

2009-06-01

Small studies have suggested that honey benefits patients with high cholesterol concentrations. The present study aimed to confirm this finding in a larger group of subjects. Sixty volunteers with high cholesterol, stratified according to gender and hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin) treatment (yes/no), were randomized to receive 75 g of honey solution or a honey-comparable sugar solution once daily over a period of 14 days. Baseline measurements, including body mass index (BMI) and lipid profile, were obtained, and subjects also completed dietary questionnaires and the Inventory for the Assessment of Negative Bodily Affect-Trait form (INKA-h) questionnaire. Measurements were repeated 2 weeks later. BMI and high-density lipoprotein (HDL) cholesterol values were significantly correlated (r = -0.487; P < .001) as were BMI and a lower ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol (r = 0.420; P < .001), meaning that subjects with a high BMI had a lower HDL cholesterol value. INKA-h scores and LDL cholesterol values were also significantly correlated (r = 0.273, P = .042). Neither solution influenced significantly cholesterol or triglyceride values in the total group; in women, however, the LDL cholesterol value increased in the sugar solution subgroup but not in the women taking honey. Although ingesting honey did not reduce LDL cholesterol values in general, women may benefit from substituting honey for sugar in their diet. Reducing the BMI lowers the LDL cholesterol value, and psychological interventions also seem important and merit further investigation.

Effects of simvastatin and ezetimibe in lowering low-density lipoprotein cholesterol in subjects with type 1 and type 2 diabetes mellitus.

PubMed

Ciriacks, Kevin; Coly, Gerard; Krishnaswami, Shanthi; Patel, Shailendra B; Kidambi, Srividya

2015-03-01

Statins are used to lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels among patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM). However, there are no studies of statin efficacy among T1DM patients. T1DM patients have higher gut cholesterol absorption than synthesis; hence cholesterol absorption inhibitors such as ezetimibe may also be effective in T1DM. Here, we compare the effects of simvastatin and ezetimibe among subjects with T1DM and T2DM. Subjects with T1DM (n=20, 45% female) or T2DM (n=27, 56% female) were assigned to alternating therapy with simvastatin (40 mg) or ezetimibe (10 mg) for 6 weeks in a crossover design. Among T2DM subjects, simvastatin lowered TC and LDL-C from the baseline (-25±4% and -40±5%, respectively, P<0.001), whereas ezetimibe was not as effective (-2±4% and -3±5%, respectively). Among T1DM subjects, both statin and ezetimibe showed significant decreases in TC and LDL-C from baseline, although ezetimibe lowered LDL-C much more than simvastatin (-32±12 (P<0.001) and -19±5% (P<0.01), respectively). Effect of simvastatin on LDL-C was much lower among T1DM subjects compared to T2DM subjects (P=0.02). This study shows that the cholesterol synthesis inhibitor simvastatin was less effective in lowering LDL-C in T1DM than T2DM subjects, whereas the cholesterol absorption inhibitor ezetimibe was at least as effective in lowering LDL-C as simvastatin among T1DM subjects.

Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV.

PubMed Central

Cohen, R D; Castellani, L W; Qiao, J H; Van Lenten, B J; Lusis, A J; Reue, K

1997-01-01

Transgenic mouse lines carrying several copies of the mouse apo A-IV gene were produced. Lipoprotein composition and function, and aortic lesion development were examined. Apo A-IV levels in the plasma of transgenic mice were elevated threefold compared with nontransgenic littermates on a chow diet, and sixfold in mice fed an atherogenic diet. Plasma concentrations of total cholesterol, HDL cholesterol, triglycerides, and free fatty acids were similar in transgenic and control mice fed a chow diet. However, with the atherogenic diet, male transgenic mice exhibited significantly higher levels of plasma triglycerides (P < 0.05), total cholesterol (P < 0.01), HDL cholesterol (P < 0.0001), and free fatty acids (P < 0.05), and lower levels of unesterified cholesterol (P < 0.05), than nontransgenic littermates. Expression of the apo A-IV transgene had a protective effect against the formation of diet-induced aortic lesions, with transgenics exhibiting lesion scores of approximately 30% those seen in control mice. HDL-sized lipoproteins isolated from transgenic mice fed the atherogenic diet promoted cholesterol efflux from cholesterol-loaded human monocytes more efficiently than comparable lipoproteins from nontransgenic counterparts. Plasma from transgenics also exhibited higher endogenous cholesterol esterification rates. Taken together, these results suggest that apo A-IV levels influence the metabolism and antiatherogenic properties of HDL. PMID:9109435

High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype.

PubMed

Halverstadt, Amy; Phares, Dana A; Ferrell, Robert E; Wilund, Kenneth R; Goldberg, Andrew P; Hagberg, James M

2003-11-01

Plasma high-density lipoprotein cholesterol (HDL-C) levels are an important independent risk factor for cardiovascular disease (CVD) that can be modified through exercise training. However, levels of HDL-C and its subfractions and their response to standardized exercise training are highly variable among individuals. Such variability suggests that levels of HDL-C, its subfractions, and their response to exercise training may be influenced by genetic variation and the interaction of that genetic variation with physical activity. The endothelial lipase gene (LIPG) may influence HDL-C metabolism and has several recently identified genetic variants. We hypothesized that the LIPG Thr111Ile polymorphism would be associated with variation in HDL-C levels and its subfractions and their response to exercise training. Eighty-three sedentary, healthy 50- to 75-year-old subjects were weight-maintained on an American Heart Association Step 1 Diet and then studied before and after aerobic exercise training. Sample size varied according to outcome measure as complete data was not available for all subjects. Initial age, body composition, and maximum oxygen consumption (V02max) did not differ between LIPG genotype groups (CC, n=41 to 44; CT/TT, n=37 to 39). Initial total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels were not significantly different between groups. The CT/TT group had lower initial HDL(2NMR)-C (12 +/- 1.0 v 17 +/- 1.1 mg/dL; P =.002) and integrated HDL(1,2NMR)-C (13 +/- 1.0 v 18 +/- 1.1 mg/dL; P=.002) levels and somewhat higher initial levels of integrated HDL(3,4,5)-C (31 +/- 2.2 v 25 +/- 2.3 mg/dL; P=.06). With exercise training, Vo2max increased, and body weight, total body fat, and visceral adipose tissue decreased similarly in both groups. With training, HDL-C levels increased twice as much (4.4 +/- 0.8 v 1.9 +/- 0.9 mg/dL; P=.04), HDL3-C levels increased almost 2-fold greater (3.8 +/- 0.7 v 2.2 +/- 0.6 mg/dL; P=.07

Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease

PubMed Central

Toth, Peter P

2016-01-01

Approximately 25% of US adults are estimated to have hypertriglyceridemia (triglyceride [TG] level ≥150 mg/dL [≥1.7 mmol/L]). Elevated TG levels are associated with increased cardiovascular disease (CVD) risk, and severe hypertriglyceridemia (TG levels ≥500 mg/dL [≥5.6 mmol/L]) is a well-established risk factor for acute pancreatitis. Plasma TG levels correspond to the sum of the TG content in TG-rich lipoproteins (TRLs; ie, very low-density lipoproteins plus chylomicrons) and their remnants. There remains some uncertainty regarding the direct causal role of TRLs in the progression of atherosclerosis and CVD, with cardiovascular outcome studies of TG-lowering agents, to date, having produced inconsistent results. Although low-density lipoprotein cholesterol (LDL-C) remains the primary treatment target to reduce CVD risk, a number of large-scale epidemiological studies have shown that elevated TG levels are independently associated with increased incidence of cardiovascular events, even in patients treated effectively with statins. Genetic studies have further clarified the causal association between TRLs and CVD. Variants in several key genes involved in TRL metabolism are strongly associated with CVD risk, with the strength of a variant’s effect on TG levels correlating with the magnitude of the variant’s effect on CVD. TRLs are thought to contribute to the progression of atherosclerosis and CVD via a number of direct and indirect mechanisms. They directly contribute to intimal cholesterol deposition and are also involved in the activation and enhancement of several proinflammatory, proapoptotic, and procoagulant pathways. Evidence suggests that non-high-density lipoprotein cholesterol, the sum of the total cholesterol carried by atherogenic lipoproteins (including LDL, TRL, and TRL remnants), provides a better indication of CVD risk than LDL-C, particularly in patients with hypertriglyceridemia. This article aims to provide an overview of the

Distribution and correlates of non-high-density lipoprotein cholesterol and triglycerides in Lebanese school children.

PubMed

Gannagé-Yared, Marie-Hélène; Farah, Vanessa; Chahine, Elise; Balech, Nicole; Ibrahim, Toni; Asmar, Nadia; Barakett-Hamadé, Vanda; Jambart, Selim

2016-01-01

The prevalence of dyslipidelmia in pediatric Middle-Eastern populations is unknown. Our study aims to investigate the distribution and correlates of non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides among Lebanese school children. A total of 969 subjects aged 8-18 years were included in the study (505 boys and 464 girls). Recruitment was done from 10 schools located in the Great Beirut and Mount-Lebanon areas. Non-fasting total cholesterol, triglycerides, and HDL-cholesterol (HDL-C) were measured. Non-HDL-C was calculated. Schools were categorized into 3 socioeconomic statuses (SESs; low, middle, and high). In the overall population, the prevalence of high non-HDL-C (>3.8 mmol/L), very high non-HDL-C (>4.9 mmol/L), and high triglycerides (>1.5 mmol/l) are respectively 9.2%, 1.24%, and 26.6%. There is no significant gender difference for non-HDL-C or triglycerides. Non-HDL-C and triglycerides are inversely correlated with age in girls (P < .0001 for both variables) but not in boys. They are also positively correlated with body mass index (BMI) in boys and girls (P < .0001 for all variables). There is no relationship between schools' socioeconomic process (SES) and non-HDL-C. However, triglycerides are higher in children from lower SES schools. After adjustment for age and body mass index (BMI), testosterone is inversely associated with triglycerides in boys (P < .0001). In a multivariate regression analysis, non-HDL-C is independently associated with age and BMI in girls (P < .0001 for both variables) but only with BMI in boys (P < .0001), whereas triglycerides are independently associated with BMI and schools' SES in both girls and boys. This study confirms, in our population, the association between obesity and both high non-HDL-C and triglycerides, and between high triglycerides and low SES. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol

PubMed Central

Infante, Rodney Elwood; Radhakrishnan, Arun

2017-01-01

Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding of post-lysosomal transport steps. Here, we establish the cholesterol-binding domain 4 of anthrolysin O (ALOD4) as a reversible inhibitor of cholesterol transport from PM to endoplasmic reticulum (ER). Using ALOD4, we: (1) deplete ER cholesterol without altering PM or overall cellular cholesterol levels; (2) demonstrate that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to suppress activation of SREBPs, halting cholesterol uptake and synthesis; and (3) determine that continuous PM-to-ER cholesterol transport allows ER to constantly monitor PM cholesterol levels, and respond rapidly to small declines in cellular cholesterol by activating SREBPs, increasing cholesterol uptake and synthesis. DOI: http://dx.doi.org/10.7554/eLife.25466.001 PMID:28414269

[Cholesterol of the high-density lipoprotein subclasses in the native inhabitants of the Chukchi National Autonomous Okrug].

PubMed

Polesskiĭ, V A; Chepurnenko, N V; Koshechkin, V A; Morozov, V V; Gerasimova, E N

1980-12-01

The authors studied the content of total cholesterol (Ch), triglycerides (TG), CS of high density lipoprotein (HDL2 and HDL3) subclasses and testosterone in blood plasma of 30-59-year-old males, natives or newcomers of Chukotsk, and compared the results with the corresponding values determined in the male population of Moscow. It was established that the mean HDL Ch concentration in blood plasma was higher and the content of TG and to a lesser degree that of total CS, was lower in the Chukchi males than in the male Moscow population and in the newcomers who were examined. It was also shown that in hypo- and hyper-alphalipoproteinemia in all groups examined, the content of HDL2 Ch changed for the most part (decreased or increased, respectively) while the level of HDL3 Ch remained relatively stable.

Distinct Lipoprotein Curves in Normal Weight, Overweight, and Obese Children and Adolescents.

PubMed

Interator, Hagar; Lebenthal, Yael; Hoshen, Moshe; Safra, Inbar; Balicer, Ran; Leshno, Moshe; Shamir, Raanan

2017-12-01

Pediatric lipoprotein curves are based on population-based samples. As obesity, may alter lipoprotein levels, cutoffs not adjusted for body mass index (BMI) are potentially inappropriate. We aimed to develop distinct serum lipid curves based on sex- and BMI-percentiles for children and adolescents. Cross-sectional analysis included all healthy children and adolescents (age range 2-17 years) with available serum lipid concentrations (n = 152,820 of approximately 1.2 million children and adolescents per study year). These children and adolescents were categorized according to sex- and age-stratified BMI-percentiles: 100,375 normal weight (5th-85th percentile), 26,028 overweight (85th-95th percentile) and 26,417 obese (≥95th percentile) individuals. Excluded were individuals with hyperlipidemia, gastrointestinal disease, thyroid disease and lipid-lowering medications. Lambda-Mu-Sigma, smoothed percentile lipid curves were computed. Obese children had a lipid profile pattern throughout childhood and adolescence similar to that of normal weight subjects but with a significant upward shift in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TGs) and a downward shift in high-density lipoprotein-cholesterol (HDL-C). Obese boys had 13 mg/dL higher TC levels (P < 0.001), 11 mg/dL higher LDL-C levels, 15 mg/dL higher non-HDL-C levels, and 5 mg/dL lower HDL-C levels (P < 0.001). Obese girls had 6 mg/dL higher TC levels, 7 mg/dL higher LDL-C levels, 11 mg/dl higher non-HDL-C levels, and 6 mg/dL lower HDL-C levels (P < 0.001). Across a large, nationally representative cohort of children and adolescents, lipoprotein levels were found to vary in relation to weight status. On the basis of these findings, it is suggested that when evaluating the lipid profile in the pediatric population, in addition to sex-based curves, clinical decision making may require

Nonlinear Associations between Plasma Cholesterol Levels and Neuropsychological Function

PubMed Central

Wendell, Carrington R.; Zonderman, Alan B.; Katzel, Leslie I.; Rosenberger, William F.; Plamadeala, Victoria V.; Hosey, Megan M.; Waldstein, Shari R.

2016-01-01

Objective Although both high and low levels of total and low-density lipoprotein (LDL) cholesterol have been associated with poor neuropsychological function, little research has examined nonlinear effects. We examined quadratic relations of cholesterol to performance on a comprehensive neuropsychological battery. Method Participants were 190 older adults (53% men, ages 54–83) free of major medical, neurologic, and psychiatric disease. Measures of fasting plasma total and high-density lipoprotein (HDL) cholesterol were assayed, and LDL cholesterol was calculated. Participants completed neuropsychological measures of attention, executive function, memory, visuospatial judgment, and manual speed/dexterity. Multiple regression analyses examined cholesterol levels as quadratic predictors of each measure of cognitive performance, with age (dichotomized as <70 vs. 70+) as an effect modifier. Results A significant quadratic effect of total cholesterol2 × age was identified for Logical Memory II (b=−.0013, p=.039), such that the 70+ group performed best at high and low levels of total cholesterol than at mid-range total cholesterol (U-shaped), and the <70 group performed worse at high and low levels of total cholesterol than at mid-range total cholesterol (inverted U-shape). Similarly, significant U- and J-shaped effects of LDL cholesterol2 × age were identified for Visual Reproduction II (b=−.0020, p=.026) and log of Trails B (b=.0001, p=.044). Quadratic associations between HDL cholesterol and cognitive performance were nonsignificant. Conclusions Results indicate differential associations between cholesterol and neuropsychological function across different ages and domains of function. High and low total and LDL cholesterol may confer both risk and benefit for suboptimal cognitive function at different ages. PMID:27280580

Nonlinear associations between plasma cholesterol levels and neuropsychological function.

PubMed

Wendell, Carrington R; Zonderman, Alan B; Katzel, Leslie I; Rosenberger, William F; Plamadeala, Victoria V; Hosey, Megan M; Waldstein, Shari R

2016-11-01

Although both high and low levels of total and low-density lipoprotein (LDL) cholesterol have been associated with poor neuropsychological function, little research has examined nonlinear effects. We examined quadratic relations of cholesterol to performance on a comprehensive neuropsychological battery. Participants were 190 older adults (53% men, ages 54-83) free of major medical, neurologic, and psychiatric disease. Measures of fasting plasma total and high-density lipoprotein (HDL) cholesterol were assayed, and LDL cholesterol was calculated. Participants completed neuropsychological measures of attention, executive function, memory, visuospatial judgment, and manual speed and dexterity. Multiple regression analyses examined cholesterol levels as quadratic predictors of each measure of cognitive performance, with age (dichotomized as <70 vs. 70+) as an effect modifier. A significant quadratic effect of Total Cholesterol² × Age was identified for Logical Memory II ( b = -.0013, p = .039), such that the 70+ group performed best at high and low levels of total cholesterol than at midrange total cholesterol (U-shaped) and the <70 group performed worse at high and low levels of total cholesterol than at midrange total cholesterol (inverted U shape). Similarly, significant U- and J-shaped effects of LDL Cholesterol² × Age were identified for Visual Reproduction II ( b = -.0020, p = .026) and log of the Trail Making Test, Part B (b = .0001, p = .044). Quadratic associations between HDL cholesterol and cognitive performance were nonsignificant. Results indicate differential associations between cholesterol and neuropsychological function across different ages and domains of function. High and low total and LDL cholesterol may confer both risk and benefit for suboptimal cognitive function at different ages. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Lipoprotein Subfractions in Metabolic Syndrome and Obesity: Clinical Significance and Therapeutic Approaches

PubMed Central

Nikolic, Dragana; Katsiki, Niki; Montalto, Giuseppe; Isenovic, Esma R.; Mikhailidis, Dimitri P.; Rizzo, Manfredi

2013-01-01

Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk. PMID:23507795

Regulation of neuronal APL-1 expression by cholesterol starvation.

PubMed

Wiese, Mary; Antebi, Adam; Zheng, Hui

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid plaques composed primarily of the amyloid-β peptide, a cleavage product of amyloid precursor protein (APP). While mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), sporadic AD has only one clear genetic modifier: the ε4 allele of the apolipoprotein E (ApoE) gene. Cholesterol starvation in Caenorhabditis elegans leads to molting and arrest phenotypes similar to loss-of-function mutants of the APP ortholog, apl-1 (amyloid precursor-like protein 1), and lrp-1 (lipoprotein receptor-related protein 1), suggesting a potential interaction between apl-1 and cholesterol metabolism. Previously, we found that RNAi knock-down of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. Here we find the same defect is recapitulated during lrp-1 knock-down and by cholesterol starvation. A cholesterol-free diet or loss of lrp-1 directly affects APL-1 levels as both lead to loss of APL-1::GFP fluorescence in neurons. However, loss of cholesterol does not affect global transcription or protein levels as seen by qPCR and Western blot. Our results show that cholesterol and lrp-1 are involved in the regulation of synaptic transmission, similar to apl-1. Both are able to modulate APL-1 protein levels in neurons, however cholesterol changes do not affect global apl-1 transcription or APL-1 protein indicating the changes are specific to neurons. Thus, regulation of synaptic transmission and molting by LRP-1 and cholesterol may be mediated by their ability to control APL-1 neuronal protein expression.

Protection by scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in hyperlipidaemic diabetic rabbit.

PubMed

Huang, H C; Weng, Y I; Lee, C R; Jan, T R; Chen, Y L; Lee, Y T

1993-12-01

1. The in vivo pharmacological effects of scoparone (6,7-dimethoxycoumarin) in a hyperlipidaemic diabetic rabbit model were investigated. 2. Three groups of rabbits were studied: (1) normal, (2) hyperlipidaemic and diabetic-untreated and (3) hyperlipidaemic and diabetic-scoparone treated. The hyperlipidaemic diabetic rabbits were fed with 1% cholesterol and treated with alloxan, a diabetogenic agent. The plasma levels of total cholesterol, total triglyceride, very low-density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were markedly increased as soon as the rabbit became diabetic at the second week. Scoparone-treatment (5 mg kg-1 day-1, s.c.) significantly reduced the plasma lipid and lipoprotein cholesterol levels of the hyperlipidaemic diabetic rabbit to 73.3% of total cholesterol, 48.3% of total triglyceride, 66.0% of VLDL cholesterol, 55.7% of LDL cholesterol and 79.5% of HDL cholesterol. 3. Six weeks after cholesterol-feeding, the aortic arch and thoracic aorta were dissected for morphological and functional studies. In vascular rings from the untreated hyperlipidaemic diabetic rabbit, there was intimal thickening with accumulation of fatty streaks, foam cells and migration of smooth muscle cells to the intima. In the rabbits treated with scoparone, there were fewer pathological morphology changes found in vascular segments than in the untreated hyperlipidaemic diabetic rabbits. 4. In the vascular reactivity experiments, the phenylephrine-induced contraction and nitroprusside induced dilatation did not differ significantly among the three rabbit groups, except that the contraction was enhanced in the thoracic aorta of hyperlipidaemic diabetic rabbits either untreated or treated withscoparone, as compared to the normal group, and the sensitivity to nitroprusside was increased in the thoracic aorta of the scoparone-treated group as compared to the untreated group.5. The endothelium

The Success Story of LDL Cholesterol Lowering.

PubMed

Pedersen, Terje R

2016-02-19

We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence. © 2016 American Heart Association, Inc.

Regulation of lecithin-cholesterol acyltransferase reaction by acyl acceptors and demonstration of its "idling" reaction.

PubMed

Czarnecka, H; Yokoyama, S

1993-09-15

The mechanism for regulation of cholesterol esterification by lecithin-cholesterol acyltransferase (LCAT) was studied using the highly isolated enzyme from pig plasma. In the reaction with phosphatidylcholine small unilamellar vesicles, cholesterol, water, diacylglycerol, and lysophosphatidylcholine were all potent acceptors of an acyl group cleaved from the sn-2 position of egg phosphatidylcholine, generating cholesteryl ester, free fatty acid, triglyceride, and phosphatidylcholine, respectively. All of these reactions required activation by human apolipoprotein A-I, suggesting that this activation leads to the deacylation of phosphatidylcholine. Those acceptors competed against each other in this vesicle reaction system, and cholesterol was the most potent acyl acceptor. Lysophosphatidylcholine that was endogenously generated by deacylation of phosphatidylcholine in the first step of the LCAT reaction was also a good acyl acceptor, showing that the reaction is always partly "idling." Bovine serum albumin partially inhibited this idling reaction in a concentration-dependent manner up to 80% at 0.60 mM. The above results were essentially reproducible with high density lipoprotein, except that cholesterol is less potent than lysophosphatidylcholine in accepting the acyl group under the condition used. Unlike the apolipoprotein A-I-activated reaction, cholesterol was esterified only slightly by the LCAT reaction on low density lipoprotein and, consequently, did not compete against lysophosphatidylcholine for generation of phosphatidylcholine. Thus, apoB may activate LCAT in a very different manner from apoA-I. The rate of esterification of lysophosphatidylcholine on low density lipoprotein was one-tenth of that on the vesicles and on high density lipoprotein. Thus, LCAT is active on low density lipoprotein but mostly idling as deacylating and reacylating glycerophospholipids.

A Spectrum of PCSK9 Alleles Contributes to Plasma Levels of Low-Density Lipoprotein Cholesterol

PubMed Central

Kotowski, Ingrid K.; Pertsemlidis, Alexander; Luke, Amy; Cooper, Richard S.; Vega, Gloria L.; Cohen, Jonathan C.; Hobbs, Helen H.

2006-01-01

Selected missense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) cause autosomal dominant hypercholesterolemia, whereas nonsense mutations in the same gene are associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C). Here, DNA sequencing and chip-based oligonucleotide hybridization were used to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n=3,543) who had the lowest (<5th percentile) and highest (>95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, 3 (R46L, L253F, and A443T) were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5% to 30%). None of the low–LDL-C variants were associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding is most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2% to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contribute to interindividual differences in LDL-C levels. These findings reveal that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and make it an attractive therapeutic target for LDL-C lowering. PMID:16465619

Diet and the role of lipoproteins, lipases, and thyroid hormones in coronary lesion growth

NASA Technical Reports Server (NTRS)

Barth, Jacques D.; Jansen, Hans; Reiber, Johan H. C.; Birkenhager, Jan C.; Kromhout, Daan

1987-01-01

The relationships between the coronary lesion growth and the blood contents of lipoprotein fractions, thyroic hormones, and the lipoprotein lipase activity were investigated in male patients with severe coronary atherosclerosis, who participated in a lipid-lowering dietary intervention program. A quantitative computer-assisted image-processing technique was used to assess the severity of coronary obstructions at the beginning of the program and at its termination two years later. Based on absolute coronary scores, patients were divided into a no-lesion growth group (14 patients) and a progression group (21 paients). At the end of the trial, the very-low-density lipoprotein cholesterol and triglycerides were found to be significantly higher, while the high-density lipoprotein cholesterol and hepatic lipase (HL) were lower in the progression group. Multivariate regression analysis showed HL to be the most important determinant of changes in coronary atherosclerotic lesions.

Intercorrelations of lipoprotein subfractions and their covariation with lifestyle factors in healthy men.

PubMed

Parlesak, Alexandr; Eckoldt, Joachim; Winkler, Karl; Bode, Christian J; Schäfer, Christian

2014-05-01

So far, little is known about the effect of nutrition and lifestyle on the composition of circulating lipoprotein subfractions. In the current study, we measured the correlations among physical activity, nutrient intake, smoking, body-mass index (BMI), and age with the concentration of triglycerides, cholesterol, phospholipids, and apolipoproteins (ApoA1, ApoA2 and ApoB) in subfractions of LDL and HDL in 265 healthy working men. Concentrations of cholesterol, phospholipids, and ApoB in small, dense atherogenic LDL particles (sdLDL) correlated negatively (p<0.001) with those of cholesterol, phospholipids, and ApoA1 in HDL2, respectively. Age correlated positively with sdLDL while increasing BMI correlated with an atherogenic shift of cholesterol, phospholipids, and ApoB from large, buoyant LDL (lbLDL) to sdLDL and decreasing concentrations of HDL2 constituents. Physical activity and alcohol intake correlated negatively with sdLDL constituents and positively with HDL2 components. Consumption of monounsaturated fatty acids (MUFA) correlated with a lower ratio of sdLDL to HDL2 cholesterol. A favorable lipoprotein subfraction profile linked to a reduced risk of cardiovascular disease in men was associated with physical activity, moderate alcohol consumption, and dietary intake of MUFA, which might be exploited in future interventions for prevention of age- and BMI-associated atherogenic shifts of lipoprotein subfractions.

Intercorrelations of lipoprotein subfractions and their covariation with lifestyle factors in healthy men

PubMed Central

Parlesak, Alexandr; Eckoldt, Joachim; Winkler, Karl; Bode, Christian J; Schäfer, Christian

2014-01-01

So far, little is known about the effect of nutrition and lifestyle on the composition of circulating lipoprotein subfractions. In the current study, we measured the correlations among physical activity, nutrient intake, smoking, body-mass index (BMI), and age with the concentration of triglycerides, cholesterol, phospholipids, and apolipoproteins (ApoA1, ApoA2 and ApoB) in subfractions of LDL and HDL in 265 healthy working men. Concentrations of cholesterol, phospholipids, and ApoB in small, dense atherogenic LDL particles (sdLDL) correlated negatively (p<0.001) with those of cholesterol, phospholipids, and ApoA1 in HDL2, respectively. Age correlated positively with sdLDL while increasing BMI correlated with an atherogenic shift of cholesterol, phospholipids, and ApoB from large, buoyant LDL (lbLDL) to sdLDL and decreasing concentrations of HDL2 constituents. Physical activity and alcohol intake correlated negatively with sdLDL constituents and positively with HDL2 components. Consumption of monounsaturated fatty acids (MUFA) correlated with a lower ratio of sdLDL to HDL2 cholesterol. A favorable lipoprotein subfraction profile linked to a reduced risk of cardiovascular disease in men was associated with physical activity, moderate alcohol consumption, and dietary intake of MUFA, which might be exploited in future interventions for prevention of age- and BMI-associated atherogenic shifts of lipoprotein subfractions. PMID:24895480

Cholesterol, APOE genotype, and Alzheimer disease

PubMed Central

Hall, K.; Murrell, J.; Ogunniyi, A.; Deeg, M.; Baiyewu, O.; Gao, S.; Gureje, O.; Dickens, J.; Evans, R.; Smith-Gamble, V.; Unverzagt, F.W.; Shen, J.; Hendrie, H.

2010-01-01

Objective To examine the relationship between cholesterol and other lipids, APOE genotype, and risk of Alzheimer disease (AD) in a population-based study of elderly Yoruba living in Ibadan, Nigeria. Methods Blood samples and clinical data were collected from Yoruba study participants aged 70 years and older (N = 1,075) as part of the Indianapolis-Ibadan Dementia Project, a longitudinal epidemiologic study of AD. Cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were measured in fasting blood samples. DNA was extracted and APOE was genotyped. Diagnoses of AD were made by consensus using National Institute of Neurologic Disorders/Stroke-Alzheimer's Disease and Related Disorders Association criteria. Results Logistic regression models showed interaction after adjusting for age and gender between APOE-ε4 genotype and biomarkers in the risk of AD cholesterol*genotype (p = 0.022), LDL*genotype (p = 0.018), and triglyceride*genotype (p = 0.036). Increasing levels of cholesterol and LDL were associated with increased risk of AD in individuals without the APOE-ε4 allele, but not in those with APOE-ε4. There was no significant association between levels of triglycerides and AD risk in those without APOE-ε4. Conclusions There was a significant interaction between cholesterol, APOE-ε4, and the risk of Alzheimer disease (AD) in the Yoruba, a population that has lower cholesterol levels and lower incidence rates of AD compared to African Americans. APOE status needs to be considered when assessing the relationship between lipid levels and AD risk in population studies. PMID:16434658

Achieving low-density lipoprotein cholesterol goals in high-risk patients in managed care: comparison of rosuvastatin, atorvastatin, and simvastatin in the SOLAR trial.

PubMed

Insull, William; Ghali, Jalal K; Hassman, David R; Y As, Joseph W; Gandhi, Sanjay K; Miller, Elinor

2007-05-01

To evaluate attainment of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein cholesterol (LDL-C) goal of less than 100 mg/dL with statin treatments in managed care patients at high risk for coronary heart disease. In a randomized, open-label, multicenter trial (SOLAR [Satisfying Optimal LDL-C ATP III goals with Rosuvastatin]) performed at 145 US clinical centers from June 5, 2002 to July 12, 2004, high-risk men and women in a managed care population received typical starting doses of rosuvastatin (10 mg/d), atorvastatin (10 mg/d), or simvastatin (20 mg/d) for 6 weeks. Those who did not meet the LDL-C target of less than 100 mg/dL at 6 weeks had their dose titrated (doubled), and all patients were followed up for another 6 weeks. A total of 1632 patients were randomized to 1 of the 3 treatment regimens. After 6 weeks, 65% of patients taking rosuvastatin reached the LDL-C target of less than 100 mg/dL vs 41% with atorvastatin and 39% with simvastatin (P<.001 vs rosuvastatin for both). After 12 weeks, 76% of patients taking rosuvastatin reached the LDL-C target of less than 100 mg/dL vs 58% with atorvastatin and 53% with simvastatin (P<.001 vs rosuvastatin for both). Reductions in the LDL-C level, total cholesterol level, non-high-density lipoprotein cholesterol (non-HDL-C) level, and non-HDL-C/HDL-C ratio were significantly greater with rosuvastatin at both 6 and 12 weeks compared with the other statins. Adverse events were similar in type and frequency in all treatment groups, and only 3% of all patients discontinued treatment because of adverse events. No myopathy was observed, no clinically important impact on renal function was attributed to study medications, and clinically important increases in serum transaminases were rare. In a managed care population, 10 mg of rosuvastatin treatment resulted in more patients reaching the NCEP ATP III LDL-C goal compared with 10 mg of atorvastatin and 20 mg of

Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis.

PubMed

Millard, E E; Srivastava, K; Traub, L M; Schaffer, J E; Ory, D S

2000-12-08

The Niemann-Pick type C1 (NPC1) protein is a key participant in intracellular trafficking of low density lipoprotein cholesterol, but its role in regulation of sterol homeostasis is not well understood. To characterize further the function of NPC1, we generated stable Chinese hamster ovary (CHO) cell lines overexpressing the human NPC1 protein (CHO/NPC1). NPC1 overexpression increases the rate of trafficking of low density lipoprotein cholesterol to the endoplasmic reticulum and the rate of delivery of endosomal cholesterol to the plasma membrane (PM). CHO/NPC1 cells exhibit a 1.5-fold increase in total cellular cholesterol and up to a 2.9-fold increase in PM cholesterol. This increase in PM cholesterol is closely paralleled by a 3-fold increase in de novo cholesterol synthesis. Inhibition of cholesterol synthesis results in marked redistribution of PM cholesterol to intracellular sites, suggesting an unsuspected role for NPC1 in internalization of PM cholesterol. Despite elevated total cellular cholesterol, CHO/NPC1 cells exhibit increased cholesterol synthesis, which may be attributable to both resistance to oxysterol suppression of sterol-regulated gene expression and to reduced endoplasmic reticulum cholesterol levels under basal conditions. Taken together, these studies provide important new insights into the role of NPC1 in the determination of the levels and distribution of cellular cholesterol.

[Characteristics of fatty acid composition of phosphatidyl cholines and sphingomyelins of low-density lipoproteins in the plasma of native inhabitants of Chukotka].

PubMed

Gerasimova, E N; Levachev, M M; Perova, N V; Nikitin, Iu P; Ozerova, I N

1986-01-01

Contents of cholesterol, triglycerides, high density lipoproteins (HDL) cholesterol as well as phospholipid and fatty acid compositions of phosphatidyl cholines and sphingomyelins in low density lipoproteins (LDL) were studied in blood plasma of Chukot aborigenes--Eskimos as compared with Moscow inhabitants. In Eskimos content of HDL cholesterol was higher but concentration of cholesterol and triglycerides was lower in blood plasma. In LDL concentration of sphingomyelins was increased and fatty acid composition of phosphatidyl cholines and sphingomyelins was altered where amount of polyunsaturated fatty acids was elevated (20:5 + 22:5 + 22:6). The specific characteristics of the LDL phospholipids observed in Eskimos might be responsible for the higher liquid properties of the surface monolayer in the lipoproteins; this alteration might be important for the lipoprotein properties and transformation as well as for the properties of membrane-bound enzymes, for synthesis of thromboxane and prostacyclins.

Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.

PubMed

Meissner, Maxi; Lombardo, Elisa; Havinga, Rick; Tietge, Uwe J F; Kuipers, Folkert; Groen, Albert K

2011-10-01

Regular physical activity decreases the risk for atherosclerosis but underlying mechanisms are not fully understood. We questioned whether voluntary wheel running provokes specific modulations in cholesterol turnover that translate into a decreased atherosclerotic burden in hypercholesterolemic mice. Male LDLR-deficient mice (8 weeks old) had either access to a voluntary running wheel for 12 weeks (RUN) or remained sedentary (CONTROL). Both groups were fed a western-type/high cholesterol diet. Running activity and food intake were recorded. At 12 weeks of intervention, feces, bile and plasma were collected to determine fecal, biliary and plasma parameters of cholesterol metabolism and plasma cytokines. Atherosclerotic lesion size was determined in the aortic root. RUN weighed less (∼13%) while food consumption was increased by 17% (p=0.004). Plasma cholesterol levels were decreased by 12% (p=0.035) and plasma levels of pro-atherogenic lipoproteins decreased in RUN compared to control. Running modulated cholesterol catabolism by enhancing cholesterol turnover: RUN displayed an increased biliary bile acid secretion (68%, p=0.007) and increased fecal bile acid (93%, p=0.009) and neutral sterol (33%, p=0.002) outputs compared to control indicating that reverse cholesterol transport was increased in RUN. Importantly, aortic lesion size was decreased by ∼33% in RUN (p=0.033). Voluntary wheel running reduces atherosclerotic burden in hypercholesterolemic mice. An increased cholesterol turnover, specifically its conversion into bile acids, may underlie the beneficial effect of voluntary exercise in mice. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-β clearance in human astrocytes.

PubMed

Fong, Lauren K; Yang, Max M; Dos Santos Chaves, Rodrigo; Reyna, Sol M; Langness, Vanessa F; Woodruff, Grace; Roberts, Elizabeth A; Young, Jessica E; Goldstein, Lawrence S B

2018-06-01

Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for de novo cholesterol biosynthesis and regulation in the brain, remains unclear. To address this, here we used CRISPR/Cas9 genome editing to generate isogenic APP-knockout (KO) human induced pluripotent stem cells (hiPSCs) and differentiated them into human astrocytes. We found that APP-KO astrocytes have reduced cholesterol and elevated levels of sterol regulatory element-binding protein (SREBP) target gene transcripts and proteins, which were both downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series harboring the APP Swedish and APP V717F variants. Only astrocytes homozygous for the APP Swedish (APP Swe/Swe ) mutation, which had reduced full-length APP (FL APP) due to increased β-secretase cleavage, recapitulated the APP-KO phenotypes. Astrocytic internalization of amyloid-β (Aβ), another ligand for low-density lipoprotein (LDL) receptors, was also impaired in APP-KO and APP Swe/Swe astrocytes. Finally, impairing cleavage of FL APP through β-secretase inhibition in APP Swe/Swe astrocytes reversed the LDL and Aβ endocytosis defects. In conclusion, FL APP is involved in the endocytosis of LDL receptor ligands and required for proper cholesterol homeostasis and Aβ clearance in human astrocytes. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Projected Real-World Effectiveness of Using Aggressive Low-Density Lipoprotein Cholesterol Targets Among Elderly Statin Users Following Acute Coronary Syndromes in Canada.

PubMed

Alter, David A; Tu, Jack V; Koh, Maria; Jackevicius, Cynthia A; Austin, Peter C; Rezai, Mohammad R; Bhatia, R Sacha; Johnston, Sharon; Udell, Jacob A; Ko, Dennis T

2018-05-12

The extent to which outcome benefits may be achieved through the implementation of aggressive low-density lipoprotein (LDL) cholesterol targets in real world settings remains unknown, especially among elderly statin users following acute coronary syndromes. A population-based cohort study consisting of 19 544 post-acute coronary syndrome statin-users aged ≥66 years between January 1, 2017 and March 31, 2014 was used to project the number of adverse outcome events (acute myocardial infarction or death from any cause) that could be prevented if all post-acute coronary syndrome elderly statin users were treated to 1 of 2 LDL cholesterol target levels (≤50 and ≤70 mg/dL). The number of preventable adverse outcomes was estimated by using model-based expected event probabilities as derived from Cox Proportional hazards models. In total, 61.6% and 25.5% of the elderly patients met LDL cholesterol targets of ≤70 and ≤50 mg/dL, respectively, based on current management. No more than 2.3 adverse events per 1000 elderly statin users (95% confidence interval: -0.7 to 5.4, P =0.62) could be prevented over 8.1 years if all patients were to be treated from current LDL cholesterol levels to either of the 2 LDL cholesterol targets of 70 or 50 mg/dL. The number of acute myocardial infarctions or death that could be prevented through the implementation of LDL cholesterol targets with statins is negligible among an elderly post-acute coronary syndrome population. Such findings may have implications for the applicability of newer agents, such as proprotein convertase subtilisin/kexin type-9- inhibitors. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance but not of β cell function in a Chinese population with different glucose tolerance status.

PubMed

Zhou, Meicen; Zhu, Lixin; Cui, Xiangli; Feng, Linbo; Zhao, Xuefeng; He, Shuli; Ping, Fan; Li, Wei; Li, Yuxiu

2016-06-07

Triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was a surrogate marker of IR; however, the relationship of TG/HDL-C with IR might vary by ethnicity. This study aims to investigate whether lipid ratios-TG/HDL-C, cholesterol/high-density lipoprotein-cholesterol (TC/HDL-C) ratio, low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol (LDL-C/HDL-C)) could be potential clinical markers of insulin resistance (IR) and β cell function and further to explore the optimal cut-offs in a Chinese population with different levels of glucose tolerance. Four hundred seventy-nine subjects without a history of diabetes underwent a 75 g 2 h Oral Glucose Tolerance Test (OGTT). New-onset diabetes (n = 101), pre-diabetes (n = 186), and normal glucose tolerance (n = 192) were screened. IR was defined by HOMA-IR > 2.69. Based on indices (HOMA-β, early-phase disposition index [DI30], (ΔIns30/ΔGlu30)/HOMA-IR and total-phase index [DI120]) that indicated different phases of insulin secretion, the subjects were divided into two groups, and the lower group was defined as having inadequate β cell compensation. Logistic regression models and accurate estimates of the areas under receiver operating characteristic curves (AUROC) were obtained. In all of the subjects, TG/HDL, TC/HDL-C, LDL-C/HDL-C, and TG were significantly associated with IR. The AUROCs of TG/HDL-C and TG were 0.71 (95 % CI: 0.66-0.75) and 0.71 (95 % CI: 0.65-0.75), respectively. The optimal cut-offs of TG/HDL-C and TG for IR diagnosis were 1.11 and 1.33 mmol/L, respectively. The AUROCs of TC/HDL-C and LDL-C/HDL-C were 0.66 and 0.65, respectively, but they were not acceptable for IR diagnosis. TG/HDL-C,LDL-C/HDL-C and TG were significantly associated with HOMA-β, but AUROCs were less than 0.50; therefore, the lipid ratios could not be predictors of basal β cell dysfunction. None of the lipid ratios was associated with early-phase insulin secretion. Only TG/HDL-C and

Effects of hormones on lipids and lipoproteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauss, R.M.

1991-12-01

Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women. In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause- Cross-sectional and longitudinal studies have suggested increases in levels of cholesterol, low density lipoproteins (LDL) and triglyceride-rich lipoproteins associated with menopause. High density lipoproteins (HDL), which are higher in women than men andmore » are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause, although small, and perhaps transient reductions in the HDL{sub 2} subfraction have been reported in relation to reduced estradiol level following menopause. Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. While there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, it is not dear to what extent exogenous hormone-induced lipoprotein changes contribute to the reduced incidence of cardiovascular disease with hormone replacement therapy.« less

The influence of a high level of corn oil on rat serum lipoproteins.

PubMed

Narayan, K A; McMullen, J J; Butler, D P; Wakefield, T; Calhoun, W K

1976-01-01

Although the stated requirement for linoleic acid in humans is less than 2% of the dietary calories, recently there has been considerable emphasis on the necessity to substitute dietary polyunsaturates for saturates in order to reduce serum cholesterol levels. In this study we have sought to determine the nutritional consequences of feeding a very high level of linoleate to rats. Three groups of thirty adult animals each were fed a semipurified diet consisting by weight of casein 17%; mineral mixture 5.5%; vitamin mixture in glucose 2.2%; cellulose fiber 3.0%; and corn oil 0% (group A), 10% (group B) or 40% (group C), which was provided at the expense of glucose. At the end of four weeks on the diets, blood was obtained in the fasting state from 16 rats in each group. The serum was ultracentrifugally fractionated into six classes of lipoproteins and analyzed for lipid composition and protein content. Disc gel electrophoresis using lipid and protein stains established that the various lipoprotein subclasses were reasonably free of adjacent density fractions. Although the total serum cholesterol levels were practically the same in the three groups, the cholesterol moiety of the major low density lipoproteins, LDL2 (d 1.019-1.050), but not of very low density lipoproteins, VLDL (d 1.006) or low density lipoproteins, LDL1 (d 1.006-1.019), was substantially and very significantly increased in rats fed the high level of corn oil as compared to the other groups. The concentration of the very low density lipoproteins was significantly lower in group C than in the groups A and B. The LDL2 concentration but not that of LDL1 was significantly greater in group C as compared to group A. The cholesterol/total lipid ratio was significantly greater in both LDL2 and LDL1 but not in VLDL of group C as compared with group A. The serum high density lipoproteins were relatively less influenced by the ingestion of an excessive level of corn oil at this time period. The serum lipoprotein

Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C.

PubMed

Chapman, M John; Assmann, Gerd; Fruchart, Jean-Charles; Shepherd, James; Sirtori, Cesare

2004-08-01

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.

PubMed

Lyu, Junfang; Yang, Eun Ju; Head, Sarah A; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo-Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O; Shim, Joong Sup

2017-11-28

Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Proprotein convertases in high-density lipoprotein metabolism.

PubMed

Choi, Seungbum; Korstanje, Ron

2013-09-18

The proprotein convertase subtilisin/kexins (PCSKs) are a serine endopeptidase family. PCSK members cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSK members show that PCSK members are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alteration of some PCSK members impairs normal molecular and physiological functions, which in turn lead to cardiovascular disease. High-density lipoprotein (HDL) is anti-atherogenic as it removes excessive amount of cholesterol from blood and peripheral tissues. Several PCSK members are involved in HDL metabolism. PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent studies in our lab found evidence that PCSK1 and PCSK9 are also involved in HDL metabolism. A mouse model carrying an amino acid substitution in PCSK1 showed an increase in serum apolipoprotein A1 (APOA1) level. Another mouse model lacking PCSK9 showed a decrease in APOE-containing HDL. In this review, we summarize the role of the five PCSK members in lipid, glucose, and bile acid (BA) metabolism, each of which can influence HDL metabolism. We propose an integrative model in which PCSK members regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport. PCSK members are considered as attractive therapeutic targets. A greater understanding of the molecular and physiological functions of PCSK members will improve therapeutic strategies and drug efficacy for cardiovascular disease where PCSK members play critical role, with fewer adverse effects.

Proprotein convertases in high-density lipoprotein metabolism

PubMed Central

2013-01-01

The proprotein convertase subtilisin/kexins (PCSKs) are a serine endopeptidase family. PCSK members cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSK members show that PCSK members are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alteration of some PCSK members impairs normal molecular and physiological functions, which in turn lead to cardiovascular disease. High-density lipoprotein (HDL) is anti-atherogenic as it removes excessive amount of cholesterol from blood and peripheral tissues. Several PCSK members are involved in HDL metabolism. PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent studies in our lab found evidence that PCSK1 and PCSK9 are also involved in HDL metabolism. A mouse model carrying an amino acid substitution in PCSK1 showed an increase in serum apolipoprotein A1 (APOA1) level. Another mouse model lacking PCSK9 showed a decrease in APOE-containing HDL. In this review, we summarize the role of the five PCSK members in lipid, glucose, and bile acid (BA) metabolism, each of which can influence HDL metabolism. We propose an integrative model in which PCSK members regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport. PCSK members are considered as attractive therapeutic targets. A greater understanding of the molecular and physiological functions of PCSK members will improve therapeutic strategies and drug efficacy for cardiovascular disease where PCSK members play critical role, with fewer adverse effects. PMID:24252756

Low-density lipoprotein reconstituted by pyropheophorbide cholesteryl oleate as target-specific photosensitizer.

PubMed

Zheng, Gang; Li, Hui; Zhang, Min; Lund-Katz, Sissel; Chance, Britton; Glickson, Jerry D

2002-01-01

To target tumors overexpressing low-density lipoprotein receptors (LDLr), a pyropheophorbide cholesterol oleate conjugate was synthesized and successfully reconstituted into the low-density lipoprotein (LDL) lipid core. Laser scanning confocal microscopy studies demonstrated that this photosensitizer-reconstituted LDL can be internalized via LDLr by human hepatoblastoma G(2) (HepG(2)) tumor cells.

Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.

PubMed

Van Rooyen, Derrick M; Larter, Claire Z; Haigh, W Geoffrey; Yeh, Matthew M; Ioannou, George; Kuver, Rahul; Lee, Sum P; Teoh, Narci C; Farrell, Geoffrey C

2011-10-01

Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse

PubMed Central

Braun, Anne; Zhang, Songwen; Miettinen, Helena E.; Ebrahim, Shamsah; Holm, Teresa M.; Vasile, Eliza; Post, Mark J.; Yoerger, Danita M.; Picard, Michael H.; Krieger, Joshua L.; Andrews, Nancy C.; Simons, Michael; Krieger, Monty

2003-01-01

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5–6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between ≈3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease. PMID:12771386

TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study).

PubMed

Meier, C; Staub, J J; Roth, C B; Guglielmetti, M; Kunz, M; Miserez, A R; Drewe, J; Huber, P; Herzog, R; Müller, B

2001-10-01

This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L-thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced [-0.24 mmol/liter, 3.8% (P = 0.015) and -0.33 mmol/liter, 8.2% (P = 0.004), respectively]. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol.

Identification of a novel polymorphism in X-linked sterol-4-alpha-carboxylate 3-dehydrogenase (Nsdhl) associated with reduced high-density lipoprotein cholesterol levels in I/LnJ mice.

PubMed

Bautz, David J; Broman, Karl W; Threadgill, David W

2013-10-03

Loci controlling plasma lipid concentrations were identified by performing a quantitative trait locus analysis on genotypes from 233 mice from a F2 cross between KK/HlJ and I/LnJ, two strains known to differ in their high-density lipoprotein (HDL) cholesterol levels. When fed a standard diet, HDL cholesterol concentration was affected by two significant loci, the Apoa2 locus on Chromosome (Chr) 1 and a novel locus on Chr X, along with one suggestive locus on Chr 6. Non-HDL concentration also was affected by loci on Chr 1 and X along with a suggestive locus on Chr 3. Additional loci that may be sex-specific were identified for HDL cholesterol on Chr 2, 3, and 4 and for non-HDL cholesterol on Chr 5, 7, and 14. Further investigation into the potential causative gene on Chr X for reduced HDL cholesterol levels revealed a novel, I/LnJ-specific nonsynonymous polymorphism in Nsdhl, which codes for sterol-4-alpha-carboxylate 3-dehydrogenase in the cholesterol synthesis pathway. Although many lipid quantitative trait locus have been reported previously, these data suggest there are additional genes left to be identified that control lipid levels and that can provide new pharmaceutical targets.

Distinct lipid/lipoprotein profiles and hormonal responsiveness in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

PubMed

Taechakraichana, N; Holinka, C F; Haines, C J; Subramaniam, R; Tian, X W; Ausmanas, M K

2007-06-01

Lipid/lipoprotein profiles, among other factors, are associated with risk of cardiovascular disease. Because cardiovascular disease varies in Asian countries, we hypothesized that lipid profiles differ in ethnic groups of postmenopausal Asian women. To add to the limited body of information currently available, we also investigated the effects of estrogen/progestin therapy on lipid/lipoprotein profiles in postmenopausal Asian women. The Pan-Asia Menopause (PAM) study was a prospective, randomized, double-blind clinical trial evaluating 1028 postmenopausal women at 22 investigational centers in 11 Asian countries/territories. Subjects were randomly assigned to one of three doses of continuous combined conjugated estrogens (CE)/medroxyprogesterone acetate (MPA): CE/MPA (in mg/day) = 0.625/2.5, 0.45/1.5 or 0.3/1.5. The treatment period, following baseline evaluations, consisted of six continuous 28-day cycles. Analysis of lipid profiles was a secondary objective of the PAM study. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density cholesterol (VLDC-C), triglycerides and lipoprotein(a) were analyzed at a central laboratory by state-of-the-art methods. Mean concentrations of total cholesterol, LDL-C, VLDL-C and triglycerides differed significantly among the nine ethnic groups of postmenopausal women. This difference was independent of body mass index and age, two factors that also influenced lipid/lipoprotein profiles. Mean HDL-C concentrations also differed, but this difference was influenced by body mass index in a weak interaction. All three doses of CE/MPA significantly lowered total cholesterol. Treatment with the high and middle doses significantly lowered LDL-C, and increased HDL-C, VLDL-C and triglycerides. The high dose produced a significant decrease in lipoprotein(a). The different lipid/lipoprotein profiles in the nine ethnic groups of postmenopausal Asian women evaluated here suggest

Cholesterol modulates the cellular localization of Orai1 channels and its disposition among membrane domains.

PubMed

Bohórquez-Hernández, A; Gratton, Enrico; Pacheco, Jonathan; Asanov, Alexander; Vaca, Luis

2017-12-01

Store Operated Calcium Entry (SOCE) is one of the most important mechanisms for calcium mobilization in to the cell. Two main proteins sustain SOCE: STIM1 that acts as the calcium sensor in the endoplasmic reticulum (ER) and Orai1 responsible for calcium influx upon depletion of ER. There are many studies indicating that SOCE is modulated by the cholesterol content of the plasma membrane (PM). However, a myriad of questions remain unanswered concerning the precise molecular mechanism by which cholesterol modulates SOCE. In the present study we found that reducing PM cholesterol results in the internalization of Orai1 channels, which can be prevented by overexpressing caveolin 1 (Cav1). Furthermore, Cav1 and Orai1 associate upon SOCE activation as revealed by FRET and coimmunoprecipitation assays. The effects of reducing cholesterol were not limited to an increased rate of Orai1 internalization, but also, affects the lateral movement of Orai1, inducing movement in a linear pattern (unobstructed diffusion) opposite to basal cholesterol conditions were most of Orai1 channels moves in a confined space, as assessed by Fluorescence Correlation Spectroscopy, Cav1 overexpression inhibited these alterations maintaining Orai1 into a confined and partially confined movement. These results not only highlight the complex effect of cholesterol regulation on SOCE, but also indicate a direct regulatory effect on Orai1 localization and compartmentalization by this lipid. Copyright © 2017 Elsevier B.V. All rights reserved.

Heart-Protective Effects of Echinodorus grandiflorus in Rabbits That Are Fed a High-cholesterol Diet.

PubMed

Gasparotto, Francielly Mourão; Lívero, Francislaine Aparecida Dos Reis; Palozi, Rhanany Allan Caloi; Ames, Maria Leticia; Nunes, Bruna; Donadel, Guilherme; Ribeiro, Rita de Cassia Lima; Lourenço, Emerson Luiz Botelho; Kassuya, Cândida Aparecida Leite; Junior, Arquimedes Gasparotto

2018-06-21

Excess weight and dyslipidemia are among the most serious health problems in Western societies. These conditions enhance the risk of cardiac disease and have been linked with a higher prevalence of cardiac arrhythmias and sudden death. The present study investigated the cardioprotective effects of Echinodorus grandiflorus on ventricular remodeling in rabbits that were fed a 1% cholesterol-rich diet. We first obtained an ethanol-soluble fraction of E. grandiflorus and performed a detailed phytochemical study by liquid chromatography-DAD/ESI-MS. For 60 days, male rabbits were fed the cholesterol-rich diet or a diet without the addition of cholesterol. After 30 days, different groups of rabbits were treated with the ethanol-soluble fraction of E. grandiflorus (10, 30, and 100 mg/kg, p. o.), simvastatin (2.5 mg/kg), or vehicle once daily for 30 days. At the end of 60 days, the serum lipoprotein ratio, electrocardiographic profile, histopathological alterations, and the cardiac antioxidant defense system were investigated. Echocardiographic analysis showed morphological and functional alterations in cholesterol-rich diet-fed animals, indicating left ventricle hypertrophy. The total cholesterol/high-density lipoprotein ratio and low-density lipoprotein/high-density lipoprotein ratio were significantly higher in cholesterol-rich diet-fed rabbits. Myocardial flaccidity, fatty degeneration, and concentric left ventricular hypertrophy were observed. An increase in lipid peroxidation levels, a decrease in superoxide dismutase activity, and a decrease in reduced glutathione levels were observed in the myocardium of all cholesterol-rich diet-fed rabbits. Treatment with the ethanol-soluble fraction of E. grandiflorus , especially the highest dose, significantly reduced all of these alterations, thus demonstrating the cardioprotective effect of the ethanol-soluble fraction of E. grandiflorus on cardiac changes that are induced by a cholesterol-rich diet. Georg Thieme Verlag

Lipoprotein lipase-dependent binding and uptake of low density lipoproteins by THP-1 monocytes and macrophages: possible involvement of lipid rafts.

PubMed

Makoveichuk, Elena; Castel, Susanna; Vilaró, Senen; Olivecrona, Gunilla

2004-11-08

Lipoprotein lipase (LPL) is produced by cells in the artery wall and can mediate binding of lipoproteins to cell surface heparan sulfate proteoglycans (HSPG), resulting in endocytosis (the bridging function). Active, dimeric LPL may dissociate to inactive monomers, the main form found in plasma. We have studied binding/internalization of human low density lipoprotein (LDL), mediated by bovine LPL, using THP-1 monocytes and macrophages. Uptake of (125)I-LDL was similar in monocytes and macrophages and was not affected by the LDL-receptor family antagonist receptor-associated protein (RAP) or by the phagocytosis inhibitor cytochalasin D. In contrast, uptake depended on HSPG and on membrane cholesterol. Incubation in the presence of dexamethasone increased the endogenous production of LPL by the cells and also increased LPL-mediated binding of LDL to the cell surfaces. Monomeric LPL was bound to the cells mostly in a heparin-resistant fashion. We conclude that the uptake of LDL mediated by LPL dimers is receptor-independent and involves cholesterol-enriched membrane areas (lipid rafts). Dimeric and monomeric LPL differ in their ability to mediate binding/uptake of LDL, probably due to different mechanisms for binding/internalization.

Glucose, lipid, and lipoprotein levels in sheep naturally infected with Fasciola hepatica.

PubMed

Kozat, Süleyman; Denizhan, Vural

2010-06-01

This study was designed to investigate serum glucose, lipid, and lipoprotein in sheep naturally infected with Fasciola hepatica. Ten healthy sheep and 15 infected with F. hepatica were used in study. Serum concentrations of total protein (TP), albumin, glucose, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoproteins (VLDL), and serum activities of AST, ALT, GGT, and LDH were measured using a Roche-Cobas Integra 800 auto-analyzer. At day 0 (prior to treatment) and on the 28th day (after treatment) the serum concentrations of TP, albumin, glucose, cholesterol, triglyceride, HDL, LDL, and VLDL values in sheep with F. hepatica were significantly lower than those of the control group, while serum activities of AST, ALT, GGT, and LDH of lambs with F. hepatica were significantly higher than those of the control group. At day 56 (after treatment), none of the variables was significantly different between control sheep and those that received treatment for fascioliasis (P > 0.05). Nutritional management may be used to reduce the impact of fascioliasis.

Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization.

PubMed

Alger, Heather M; Brown, J Mark; Sawyer, Janet K; Kelley, Kathryn L; Shah, Ramesh; Wilson, Martha D; Willingham, Mark C; Rudel, Lawrence L

2010-05-07

Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease.

Influence of liver cancer on lipid and lipoprotein metabolism

PubMed Central

Jiang, Jingting; Nilsson-Ehle, Peter; Xu, Ning

2006-01-01

Liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. This has been attributed to the high incidence of hepatitis B infection. Hepatitis B proteins, such as the hepatitis B X protein (HBx) that is large hepatitis B surface protein could regulate transcription of many candidate genes for liver carcinogenesis. It has known that patients who suffered from acute hepatitis B could have lipid disorders such as decreased plasma level of high-density lipoproteins (HDL). Furthermore, aberrations of lipid metabolism are often seen in the chronic hepatitis B infection. Plasma lipid profiles could be changed under HCC. In majority of the reports in HCC, plasma levels of triglycerides (TG), cholesterol, free fatty acids (FFA), HDL, low-density lipoproteins (LDL), lipoprotein (a) (Lp(a)), apolipoprotein AI (apoAI) and apoB were slight to significantly decreased, however, in some cases plasma levels of TG and Lp(a) might be increased. It has been suggested that analysis of plasma levels of lipids, lipoproteins and apolipoproteins in the patients suffered from HCC reflects on the hepatic cellular impairment status. Studies revealed that alterations seen in the plasma levels of lipids, lipoproteins and apolipoproteins reflecting patients' pathologic conditions. Decreased serum levels of cholesterol and apoAI may indicate a poor prognosis. Human leukaemic cells and certain tumor tissues have a higher receptor-mediated uptake of HDL and LDL than the corresponding normal cells or tissues. LDL and HDL have therefore been proposed as a carrier for the water-insoluble anti-cancer agents. PMID:16515689

The monocyte counts to HDL cholesterol ratio in obese and lean patients with polycystic ovary syndrome.

PubMed

Usta, Akin; Avci, Eyup; Bulbul, Cagla Bahar; Kadi, Hasan; Adali, Ertan

2018-04-10

Women with polycystic ovary syndrome are more likely to suffer from obesity, insulin resistance, and chronic low-grade inflammation. In fact, the excessive activation of monocytes exacerbates oxidative stress and inflammation. However, high-density lipoprotein cholesterol neutralizes the pro-inflammatory and pro-oxidant effects of monocytes. The aim of this study is to investigate whether monocyte counts to high-density lipoprotein cholesterol ratio can predict the inflammatory condition in patients with polycystic ovary syndrome. In this cross-sectional study, a total of 124 women (61 of them with polycystic ovary syndrome and 63 age-matched healthy volunteers) were included in the study population. Obese polycystic ovary syndrome patients (n = 30) with a body mass index of ≥25 kg/m 2 and lean polycystic ovary syndrome patients (n = 31) with a body mass index of < 25 kg/m 2 were compared to age-and body mass index-matched healthy subjects (30 obese and 33 non-obese). The monocyte counts to high density lipoprotein cholesterol values in women with polycystic ovary syndrome were significantly higher than in control subjects (p = 0.0018). Moreover, a regression analysis revealed that body mass index, the homeostasis model assessment of insulin resistance and the high sensitivity C-reactive protein levels were confounding factors that affected the monocyte counts to high density lipoprotein cholesterol values. Additionally, a univariate and multivariate logistic regression analysis demonstrated that the increased monocyte counts to high density lipoprotein cholesterol values were more sensitive than the other known risk factors (such as increased body mass index, homeostasis model assessment of insulin resistance and high sensitive C-reactive protein levels) in the prediction of the inflammation in patients with polycystic ovary syndrome. The present study demonstrated that the monocyte count to high density lipoprotein cholesterol may be a novel and

Dietary supplementation with d-tagatose in subjects with type 2 diabetes leads to weight loss and raises high-density lipoprotein cholesterol.

PubMed

Donner, Thomas W; Magder, Laurence S; Zarbalian, Kiarash

2010-12-01

Oral d-tagatose (d-tag) attenuates the rise in plasma glucose during an oral glucose tolerance test in subjects with type 2 diabetes mellitus (DM) and reduces food intake in healthy human subjects. A reduction in food consumption and less weight gain occur in rats fed tagatose. This pilot study explored the metabolic effects of d-tag given daily to 8 human subjects with type 2 DM for 1 year. We hypothesized that this treatment period would lead to weight loss and improvements in glycated hemoglobin and the lipid profile. A 2-month run-in period was followed by a 12-month treatment period when 15 g of oral d-tag was taken 3 times daily with food. No serious adverse effects were seen during the 12-month treatment period. Ten of the initially 12 recruited subjects experienced gastrointestinal side effects that tended to be mild and transient. When 3 subjects were excluded who had oral diabetes, medications added and/or dosages increased during the study and mean (SD) body weight declined from 108.4 (9.0) to 103.3 (7.3) kg (P = .001). Glycated hemoglobin fell nonsignificantly from 10.6% ± 1.9% to 9.6% ± 2.3% (P = .08). High-density lipoprotein cholesterol progressively rose from a baseline level of 30.5 ± 15.8 to 41.7 ± 12.1 mg/dL at month 12 in the 6 subjects who did not have lipid-modifying medications added during the study (P < .001). Significant improvements in body weight and high-density lipoprotein cholesterol in this pilot study suggest that d-tag may be a potentially useful adjunct in the management of patients with type 2 DM. Copyright © 2010 Elsevier Inc. All rights reserved.

Cholesterol in islet dysfunction and type 2 diabetes

PubMed Central

Brunham, Liam R.; Kruit, Janine K.; Verchere, C. Bruce; Hayden, Michael R.

2008-01-01

Type 2 diabetes (T2D) frequently occurs in the context of abnormalities of plasma lipoproteins. However, a role for elevated levels of plasma cholesterol in the pathogenesis of this disease is not well established. Recent evidence suggests that alterations of plasma and islet cholesterol levels may contribute to islet dysfunction and loss of insulin secretion. A number of genes involved in lipid metabolism have been implicated in T2D. Recently an important role for ABCA1, a cellular cholesterol transporter, has emerged in regulating cholesterol homeostasis and insulin secretion in pancreatic β cells. Here we review the impact of cholesterol metabolism on islet function and its potential relationship to T2D. PMID:18246189

Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice.

PubMed

Xie, Ping; Jia, Lin; Ma, Yinyan; Ou, Juanjuan; Miao, Hongming; Wang, Nanping; Guo, Feng; Yazdanyar, Amirfarbod; Jiang, Xian-Cheng; Yu, Liqing

2013-05-01

Controversies have arisen from recent mouse studies about the essential role of biliary sterol secretion in reverse cholesterol transport (RCT). The objective of this study was to examine the role of biliary cholesterol secretion in modulating macrophage RCT in Niemann-Pick C1-Like 1 (NPC1L1) liver only (L1(LivOnly)) mice, an animal model that is defective in both biliary sterol secretion and intestinal sterol absorption, and determine whether NPC1L1 inhibitor ezetimibe facilitates macrophage RCT by inhibiting hepatic NPC1L1. L1(LivOnly) mice were generated by crossing NPC1L1 knockout (L1-KO) mice with transgenic mice overexpressing human NPC1L1 specifically in liver. Macrophage-to-feces RCT was assayed in L1-KO and L1(LivOnly) mice injected intraperitoneally with [(3)H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [(3)H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1(LivOnly) mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [(3)H]-tracer in the neutral sterol fraction in L1(LivOnly) mice. High-density lipoprotein kinetic studies showed that L1(LivOnly) mice compared with L1-KO mice had a significantly reduced fractional catabolic rate without altered hepatic and intestinal uptake of high-density lipoprotein-cholesterol ether. In mice lacking intestinal cholesterol absorption, macrophage-to-feces RCT depends on efficient biliary sterol secretion, and ezetimibe promotes macrophage RCT by inhibiting hepatic NPC1L1 function.

Evaluation of Monocyte to High-Density Lipoprotein Cholesterol Ratio in the Presence and Severity of Metabolic Syndrome.

PubMed

Uslu, Ali Ugur; Sekin, Yahya; Tarhan, Gulten; Canakcı, Nuray; Gunduz, Mehmet; Karagulle, Mustafa

2017-01-01

Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a systemic inflammatory marker, and recently, it has been used quite commonly for the assessment of inflammation in cardiovascular disorders. The aim of the present study is to investigate the relevance of MHR as a marker to assess metabolic syndrome (MetS) and MetS severity in clinical practice. A total of 147 patients with MetS who were diagnosed according to National Cholesterol Education Program Adult Treatment Panel III criteria and 134 healthy controls, matched for age and gender, were included in our retrospective study. MHR values were 13.15 ± 6.07 for patients with MetS and 9.74 ± 5.24 for the control group. MHR values of the patients were found to be statistically significantly higher than the control group ( P < .0001). MHR showed a significantly positive correlation with the severity of MetS ( r = .429; P < .0001). When patients with MetS were assessed with MHR in the study population, receiver-operating characteristic curve analysis yielded a cutoff value of 9.36 with a sensitivity of 72%, a specificity of 61%, and a P value <.0001. In logistic regression analyses of MetS with several variables, MHR remained as an independent predictor of MetS (95% CI: 0.721-0.945, P = .005). MHR might be an available and useful inflammatory marker to evaluate patients with MetS and disease severity.

Effects of Ginger on Serum Lipids and Lipoproteins in Peritoneal Dialysis Patients: A Randomized Controlled Trial.

PubMed

Tabibi, Hadi; Imani, Hossein; Atabak, Shahnaz; Najafi, Iraj; Hedayati, Mehdi; Rahmani, Leila

2016-01-01

♦ In peritoneal dialysis (PD) patients, one of the major risk factors for cardiovascular disease is lipid abnormalities. This study was designed to investigate the effects of ginger supplementation on serum lipids and lipoproteins in PD patients. ♦ In this randomized, double-blind, placebo-controlled trial, 36 PD patients were randomly assigned to either the ginger or the placebo group. The patients in the ginger group received 1,000 mg ginger daily for 10 weeks, while the placebo group received corresponding placebos. At baseline and at the end of week 10, 7 mL of blood were obtained from each patient after a 12- to 14-hour fast, and serum concentrations of triglyceride, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and lipoprotein (a) [Lp (a)] were measured. ♦ Serum triglyceride concentration decreased significantly up to 15% in the ginger group at the end of week 10 compared with baseline (p < 0.01), and the reduction was significant in comparison with the placebo group (p < 0.05). There were no significant differences between the 2 groups in mean changes of serum total cholesterol, LDL-C, HDL-C, and Lp (a). ♦ This study indicates that daily administration of 1,000 mg ginger reduces serum triglyceride concentration, which is a risk factor for cardiovascular disease, in PD patients. Copyright © 2016 International Society for Peritoneal Dialysis.

Body mass index and glycemic control influence lipoproteins in children with type 1 diabetes.

PubMed

Vaid, Shalini; Hanks, Lynae; Griffin, Russell; Ashraf, Ambika P

2016-01-01

Patients with type 1 diabetes mellitus (T1DM) have an extremely high risk of cardiovascular disease (CVD) morbidity and mortality. It is well known that dyslipidemia is a subclinical manifestation of atherosclerosis. To analyze presence and predicting factors of lipoprotein abnormalities prevalent in children with T1DM and whether race-specific differences exist between non-Hispanic white (NHW) and non-Hispanic black (NHB) in the lipoprotein characteristics. A retrospective electronic chart review including 600 (123 NHB and 477 NHW) T1DM patients aged 7.85 ± 3.75 years who underwent lipoprotein analysis. Relative to NHW counterparts, NHB T1DM subjects had a higher HbA1c, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), apoB 100, lipoprotein (a), and high-density lipoprotein cholesterol (HDL-c), HDL-2, and HDL-3. Body mass index (BMI) was positively associated with TC, LDL-c, apoB 100, and non-HDL-c and inversely associated with HDL, HDL-2, and HDL-3. HbA1c was positively associated with TC, LDL-c, apoB 100, non-HDL-c, and HDL-3. Multilinear regression analysis demonstrated that HbA1c was positively associated with apoB 100 in both NHB and NHW, and BMI was a positive determinant of apoB 100 in NHW only. Poor glycemic control and high BMI may contribute to abnormal lipoprotein profiles. Glycemic control (in NHB and NHW) and weight management (in NHW) may have significant implications in T1DM. ApoB 100 concentrations in subjects with T1DM were determined by modifiable risk factors, BMI, HbA1C, and blood pressure, indicating the importance of adequate weight, glycemic, and blood pressure control for better diabetes care and likely lower CVD risk. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels.

PubMed

Cox, C; Sutherland, W; Mann, J; de Jong, S; Chisholm, A; Skeaff, M

1998-09-01

The aim of this present study was to determine plasma levels of lathosterol, lipids, lipoproteins and apolipoproteins during diets rich in butter, coconut fat and safflower oil. The study consisted of sequential six week periods of diets rich in butter, coconut fat then safflower oil and measurements were made at baseline and at week 4 in each diet period. Forty-one healthy Pacific island polynesians living in New Zealand participated in the trial. Subjects were supplied with some foods rich in the test fats and were given detailed dietary advice which was reinforced regularly. Plasma lathosterol concentration (P < 0.001), the ratio plasma lathosterol/cholesterol (P=0.04), low density lipoprotein (LDL) cholesterol (P<0.001) and apoB (P<0.001) levels were significantly different among the diets and were significantly lower during coconut and safflower oil diets compared with butter diets. Plasma total cholesterol, HDL cholesterol and apoA-levels were also significantly (P< or =0.001) different among the diets and were not significantly different between buffer and coconut diets. These data suggest that cholesterol synthesis is lower during diets rich in coconut fat and safflower oil compared with diets rich in butter and might be associated with lower production rates of apoB-containing lipoproteins.

The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FER(HDL)).

PubMed

Dobiásová, M; Frohlich, J

2001-10-01

To evaluate if logarithm of the ratio of plasma concentration of triglycerides to HDL-cholesterol (Log[TG/HDL-C]) correlates with cholesterol esterification rates in apoB-lipoprotein-depleted plasma (FER(HDL)) and lipoprotein particle size. We analyzed previous data dealing with the parameters related to the FER(HDL) (an indirect measure of lipoprotein particle size). In a total of 1433 subjects from 35 cohorts with various risk of atherosclerosis (cord plasma, children, healthy men and women, pre- and postmenopausal women, patients with hypertension, type 2 diabetes, dyslipidemia and patients with positive or negative angiography findings) were studied. The analysis revealed a strong positive correlation (r = 0.803) between FER(HDL) and Log(TG/HDL-C). This parameter, which we propose to call "atherogenic index of plasma" (AIP) directly related to the risk of atherosclerosis in the above cohorts. We also confirmed in a cohort of 35 normal subjects a significant inverse correlation of LDL size with FER(HDL) (r = -0.818) and AIP (r = -0.776). Values of AIP correspond closely to those of FER(HDL) and to lipoprotein particle size and thus could be used as a marker of plasma atherogenicity.

Taiwanese female vegetarians have lower lipoprotein-associated phospholipase A2 compared with omnivores.

PubMed

Chen, Chih-Wei; Lin, Chih-Ta; Lin, Ying-Lung; Lin, Tin-Kwang; Lin, Chin-Lon

2011-01-01

Many studies supported that vegetarians have a lower risk of cardiac diseases and mortality, partly due to better blood pressure and serum cholesterol profiles. However, the inflammatory markers, especially lipoprotein-associated phospholipase A2 (Lp-PLA2), have not been well-studied. This study aimed to compare inflammatory markers and conventional risk factors between vegetarians and omnivores. One hundred and seventy-three vegetarians and 190 omnivores were studied. Fasting blood samples were obtained to compare levels of glucose, total cholesterol, triacylglycerol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, homocysteine, Lp-PLA2 activity, and high-sensitivity C-reactive protein (hs-CRP). Vegetarians had higher serum levels of the following markers: hs-CRP (1.8 ± 3.4 vs. 1.2 1.8 mg/L, respectively; p = 0.05), homocysteine (9.39 ± 3.22 vs. 7.62 ± 2.41 μmol/L, respectively; p < 0.01), and triacylglycerol (96.91 ± 59.56 vs. 84.66 ± 43.24 mg/dL, respectively; p < 0.05). Vegetarians also had lower levels of Lp-PLA2 (18.32 ± 7.19 10-3 μmol/min/mL vs. 20.22 8.13 10-3 μmol/min/mL; p < 0.05), total cholesterol (180.62 ± 36.55 mg/dL vs. 192.73 ± 36.57 mg/dL; p < 0.01), LDL cholesterol (118.15 ± 32.8 vs. 126.41 ± 34.28 mg/dL; p < 0.05), and HDL cholesterol (55.59 ± 13.30 vs. 62.09 ± 14.52 mg/dL, p < 0.01). Multivariate analyses demonstrated that a vegetarian diet increases the chances for high serum hs-CRP and low Lp-PLA2 activity. In addition to lower total cholesterol, LDL-cholesterol, and HDL-cholesterol, Taiwanese female vegetarians have lower serum Lp-PLA2 activity but higher levels of hs-CRP, homocysteine, and triacylglyerol. It might be due to geographic differences of vegetarian diets, and further studies are needed.

Two-Compartment Model as a Teaching Tool for Cholesterol Homeostasis

ERIC Educational Resources Information Center

Wrona, Artur; Balbus, Joanna; Hrydziuszko, Olga; Kubica, Krystian

2015-01-01

Cholesterol is a vital structural and functional molecule in the human body that is only slightly soluble in water and therefore does not easily travels by itself in the bloodstream. To enable cholesterol's targeted delivery to cells and tissues, it is encapsulated by different fractions of lipoproteins, complex particles containing both proteins…

[The role of structural heterogeneity of circulating lipids in the regulation of lipoprotein metabolism in the plasma and lymph in hypercholesterolemia in dogs].

PubMed

Kosukhin, A B; Akhmetova, B S

1986-01-01

Fatty acid spectrum of lipoproteins was studied in intestinal steam lymph and blood plasma of dogs with alimentary hypercholesterolemia. Mechanism of cholesterol accumulation in blood plasma appears to relate to increase in content of cholesterol palmitate which is secreted from intestine into lymph and hydrolyzed slowly in liver tissue. Alterations in composition of fatty acid acyls of cholesterol esters, of phosphatidyl cholines and triacyl glycerides as well as effect of these alterations on the lecithin-cholesterol acyl-transferase reaction and lipoprotein lipolysis are discussed.

Dietary isohumulones, the bitter components of beer, raise plasma HDL-cholesterol levels and reduce liver cholesterol and triacylglycerol contents similar to PPARalpha activations in C57BL/6 mice.

PubMed

Miura, Yutaka; Hosono, Mayu; Oyamada, Chiaki; Odai, Hideharu; Oikawa, Shinichi; Kondo, Keiji

2005-04-01

The effects of dietary isohumulones, the main components accounting for the bitter taste of beer, on lipid metabolism were examined. Young female C57BL/6N mice were fed diets containing isomerized hop extract (IHE), which consists mainly of isohumulones. Administration of IHE with an atherogenic (high-fat and high-cholesterol) diet for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P<0.01), along with a concomitant reduction in the atherosclerosis index, an increase in liver weight and a decrease in body weight gain in a dose-dependent manner. When animals received IHE with either a cholesterol or a basal diet for 1 week, significant decreases in the liver content of cholesterol (P<0.01) and triacylglycerol (cholesterol diet, P<0.01) were observed. Quantitative analyses of hepatic mRNA levels revealed that IHE administration resulted in up-regulation of mRNA for acyl-CoA oxidase, acyl-CoA synthetase, hydroxymethylglutaryl-CoA synthetase, lipoprotein lipase and fatty acid transport protein, and down-regulation of mRNA for Apo CIII and Apo AI. Administration of purified isohumulones effectively resulted in the same changes as IHE. Administration of fenofibrate, an agonist for PPARalpha, with a cholesterol diet caused marked hepatomegaly, an increase in plasma HDL-cholesterol, a decrease in hepatic cholesterol content, and alterations in hepatic mRNA levels similar to those observed in mice given IHE. Taken together, these results suggest that the modulation of lipid metabolism observed in mice fed diets containing isohumulones is, at least in part, mediated by activation of PPARalpha.

Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion.

PubMed

Marshall, Stephanie M; Gromovsky, Anthony D; Kelley, Kathryn L; Davis, Matthew A; Wilson, Martha D; Lee, Richard G; Crooke, Rosanne M; Graham, Mark J; Rudel, Lawrence L; Brown, J Mark; Temel, Ryan E

2014-01-01

The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼ 2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.

High plasma level of remnant-like particle cholesterol in the metabolic syndrome.

PubMed

Satoh, Akira; Adachi, Hisashi; Tsuruta, Makoto; Hirai, Yuji; Hiratsuka, Akiko; Enomoto, Mika; Furuki, Kumiko; Hino, Asuka; Takeuchi, Tomohiro; Imaizumi, Tsutomu

2005-10-01

The metabolic syndrome is associated with a high incidence of cardiovascular disease even when the abnormalities present in the syndrome are mild. The underlying mechanism of the metabolic syndrome has not been elucidated. We investigated whether a strong atherogenic lipoprotein, remnant-like particle (RLP) lipoprotein cholesterol, is elevated in the metabolic syndrome. We performed a health examination among the residents of a rural community in Japan. Complete datasets, including fasting RLP cholesterol levels, were obtained in 1,261 subjects (509 men and 752 women) without diabetes and who were not taking lipid-lowering drugs. The subjects' medical history, use of alcohol, and smoking habits were ascertained by a questionnaire. All of the components of the metabolic syndrome were significantly related to RLP cholesterol by univariate analysis. Total cholesterol and smoking habits were also positively associated with RLP cholesterol. The subjects with the metabolic syndrome showed only mild abnormalities of each component. When RLP cholesterol levels were stratified by the number of the components of the metabolic syndrome, there was a strong association between RLP cholesterol levels and the number of components (P < 0.001 and F = 72.7). RLP cholesterol levels are elevated in the metabolic syndrome, and this elevation may underlie the high incidence of cardiovascular disease in the metabolic syndrome.

Pharmacologic management of isolated low high-density lipoprotein syndrome.

PubMed

Bermúdez, Valmore; Cano, Raquel; Cano, Clímaco; Bermúdez, Fernando; Arraiz, Nailet; Acosta, Luis; Finol, Freddy; Pabón, María Rebeca; Amell, Anilsa; Reyna, Nadia; Hidalgo, Joaquin; Kendall, Paúl; Manuel, Velasco; Hernández, Rafael

2008-01-01

High-density lipoprotein (HDL) cholesterol is a heterogeneous group of lipoproteins exhibiting a variety of properties like prostacyclin production stimulation, decrease in platelet aggregation, endothelial cell apoptosis inhibition, and low-density lipoprotein oxidation blockade. Epidemiologic studies have shown an inverse relation between HDL cholesterol levels and cardiovascular risk. Low HDL cholesterol is associated with increased risk for myocardial infarction, stroke, sudden death, peripheral artery disease, and postangioplasty restenosis. In contrast, high HDL levels are associated with longevity and protection against atherosclerotic disease development. Given the evolving epidemic of obesity, diabetes mellitus, and metabolic syndrome, the prevalence of low HDL will continue to rise. In the United States, low HDL is present in 35% of men, 15% of women, and approximately 63% of patients with coronary artery disease. Data extracted from the Framingham study highlight that 1-mg increase in HDL levels decreases by 2% to 3% the risk of cardiovascular disease. There is no doubt regarding clinical importance about isolated low HDL, but relatively few clinicians consider a direct therapeutic intervention of this dyslipidemia. In this sense, lifestyle measures should be the first-line strategy to manage low HDL levels. On the other hand, pharmacologic options include niacin, fibrates, and statins. Fibrates appear to reduce risk preferentially in patients with low HDL with metabolic syndrome, whereas statins reduce risk across all levels of HDL. Torcetrapib, a cholesteryl esters transfer protein inhibitor, represented a hope to raise this lipoprotein; however, all clinical trials on this drug had ceased after ILLUMINATE, RADIANCE and ERASE trials had recorded an increase in mortality, rates of myocardial infarction, angina, and heart failure. In the near future, drugs as beta-glucans, Apo-A1 mimetic peptides, and ACAT inhibitors, are the new promises to treat this

Effect of different fat-enriched meats on non-cholesterol sterols and oxysterols as markers of cholesterol metabolism: Results of a randomized and cross-over clinical trial.

PubMed

Baila-Rueda, L; Mateo-Gallego, R; Pérez-Calahorra, S; Lamiquiz-Moneo, I; de Castro-Orós, I; Cenarro, A; Civeira, F

2015-09-01

Different kinds of fatty acids can affect the synthesis, absorption, and elimination of cholesterol. This study was carried out to assess the associations of cholesterol metabolism with the intake of two meats with different fatty acid composition in healthy volunteers. The study group was composed of 20 subjects (12 males and eight females; age, 34.4 ± 11.6 years; body mass index (BMI), 23.5 ± 2.3 kg/m(2); low-density lipoprotein (LDL) cholesterol, 2.97 ± 0.55 mmol/l; high-density lipoprotein (HDL) cholesterol, 1.61 ± 0.31 mmol/l; triglycerides (TG), 1.06 ± 0.41 mmol/l) who completed a 30-day randomized and cross-over study to compare the cholesterol metabolism effect of 250 g of low-fat lamb versus 250 g of high-fat lamb per day in their usual diet. Cholesterol absorption, synthesis, and elimination were estimated from the serum non-cholesterol sterol and oxysterol concentrations analyzed by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). No changes in weight, plasma lipids, or physical activity were observed across the study. Cholesterol intestinal absorption was decreased with both diets. Cholesterol synthesis and elimination decreased during the low-fat lamb dietary intervention (ρ = 0.048 and ρ = 0.005, respectively). Acute changes in the diet fat content modify the synthesis, absorption, and biliary elimination of cholesterol. These changes were observed even in the absence of total and LDL cholesterol changes in plasma. ClinicalTrials.gov PRS, NCT02259153. Copyright © 2015 Elsevier B.V. All rights reserved.

Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

PubMed

Lambert, G; Sakai, N; Vaisman, B L; Neufeld, E B; Marteyn, B; Chan, C C; Paigen, B; Lupia, E; Thomas, A; Striker, L J; Blanchette-Mackie, J; Csako, G; Brady, J N; Costello, R; Striker, G E; Remaley, A T; Brewer, H B; Santamarina-Fojo, S

2001-05-04

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

Changes in cholesterol homeostasis modify the response of F1B hamsters to dietary very long chain n-3 and n-6 polyunsaturated fatty acids

PubMed Central

2011-01-01

Background The plasma lipoprotein response of F1B Golden-Syrian hamsters fed diets high in very long chain (VLC) n-3 polyunsaturated fatty acids (PUFA) is paradoxical to that observed in humans. This anomaly is attributed, in part, to low lipoprotein lipase activity and is dependent on cholesterol status. To further elucidate the mechanism(s) for these responses, hamsters were fed diets containing supplemental fish oil (VLC n-3 PUFA) or safflower oil (n-6 PUFA) (both 10% [w/w]) and either cholesterol-supplemented (0.1% cholesterol [w/w]) or cholesterol-depleted (0.01% cholesterol [w/w] and 10 days prior to killing fed 0.15% lovastatin+2% cholestyramine [w/w]). Results Cholesterol-supplemented hamsters fed fish oil, relative to safflower oil, had higher non-high density lipoprotein (HDL) cholesterol and triglyceride concentrations (P < 0.001) which were associated with lower hepatic low density lipoprotein (LDL) receptor, sterol regulatory element binding protein (SREBP)-1c and acyl-CoA: cholesterol acyl transferase-2 (ACAT) mRNA and protein (p < 0.05), and higher hepatic apolipoprotein (apo) B-100 and apo E protein levels. In contrast, cholesterol-depleted hamsters fed fish oil, relative to safflower oil, had lower non-HDL cholesterol and triglyceride concentrations (P < 0.001) which were associated with lower hepatic SREBP-1c (p < 0.05) but not apo B-100, apo E or ACAT-2 mRNA or protein levels. Independent of cholesterol status, fish oil fed hamsters had lower HDL cholesterol concentrations (p < 0.001), which were associated with lower hepatic apoA-I protein levels (p < 0.05). Conclusion These data suggest disturbing cholesterol homeostasis in F1B hamsters alters their response to dietary fatty acids, which is reflected in altered plasma lipoprotein patterns and regulation of genes associated with their metabolism. PMID:22018327

Changes in cholesterol homeostasis modify the response of F1B hamsters to dietary very long chain n-3 and n-6 polyunsaturated fatty acids.

PubMed

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

2011-10-21

The plasma lipoprotein response of F1B Golden-Syrian hamsters fed diets high in very long chain (VLC) n-3 polyunsaturated fatty acids (PUFA) is paradoxical to that observed in humans. This anomaly is attributed, in part, to low lipoprotein lipase activity and is dependent on cholesterol status. To further elucidate the mechanism(s) for these responses, hamsters were fed diets containing supplemental fish oil (VLC n-3 PUFA) or safflower oil (n-6 PUFA) (both 10% [w/w]) and either cholesterol-supplemented (0.1% cholesterol [w/w]) or cholesterol-depleted (0.01% cholesterol [w/w] and 10 days prior to killing fed 0.15% lovastatin+2% cholestyramine [w/w]). Cholesterol-supplemented hamsters fed fish oil, relative to safflower oil, had higher non-high density lipoprotein (HDL) cholesterol and triglyceride concentrations (P < 0.001) which were associated with lower hepatic low density lipoprotein (LDL) receptor, sterol regulatory element binding protein (SREBP)-1c and acyl-CoA: cholesterol acyl transferase-2 (ACAT) mRNA and protein (p < 0.05), and higher hepatic apolipoprotein (apo) B-100 and apo E protein levels. In contrast, cholesterol-depleted hamsters fed fish oil, relative to safflower oil, had lower non-HDL cholesterol and triglyceride concentrations (P < 0.001) which were associated with lower hepatic SREBP-1c (p < 0.05) but not apo B-100, apo E or ACAT-2 mRNA or protein levels. Independent of cholesterol status, fish oil fed hamsters had lower HDL cholesterol concentrations (p < 0.001), which were associated with lower hepatic apoA-I protein levels (p < 0.05). These data suggest disturbing cholesterol homeostasis in F1B hamsters alters their response to dietary fatty acids, which is reflected in altered plasma lipoprotein patterns and regulation of genes associated with their metabolism.

2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice.

PubMed

Andersen, Charlotte; Schjoldager, Janne G; Tortzen, Christian G; Vegge, Andreas; Hufeldt, Majbritt R; Skaanild, Mette T; Vogensen, Finn K; Kristiansen, Karsten; Hansen, Axel K; Nielsen, John

2013-01-01

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.

2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

PubMed Central

Andersen, Charlotte; Schjoldager, Janne G.; Tortzen, Christian G.; Vegge, Andreas; Hufeldt, Majbritt R.; Skaanild, Mette T.; Vogensen, Finn K.; Kristiansen, Karsten; Hansen, Axel K.; Nielsen, John

2013-01-01

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice. PMID:23738334

Infection of Hepatocytes With HCV Increases Cell Surface Levels of Heparan Sulfate Proteoglycans, Uptake of Cholesterol and Lipoprotein, and Virus Entry by Up-regulating SMAD6 and SMAD7.

PubMed

Zhang, Fang; Sodroski, Catherine; Cha, Helen; Li, Qisheng; Liang, T Jake

2017-01-01

The signaling molecule and transcriptional regulator SMAD6, which inhibits the transforming growth factor β signaling pathway, is required for infection of hepatocytes by hepatitis C virus (HCV). We investigated the mechanisms by which SMAD6 and another inhibitory SMAD (SMAD7) promote HCV infection in human hepatoma cells and hepatocytes. We infected Huh7 and Huh7.5.1 cells and primary human hepatocytes with Japanese fulminant hepatitis-1 (JFH1) HCV cell culture system (HCVcc). We then measured HCV binding, intracellular levels of HCV RNA, and expression of target genes. We examined HCV entry in HepG2/microRNA (miR) 122/CD81 cells, which support entry and replication of HCV, were transfected these cells with small interfering RNAs targeting inhibitory SMADs to analyze gene expression profiles. Uptake of labeled low-density lipoprotein (LDL) and cholesterol was measured. Cell surface proteins were quantified by flow cytometry. We obtained liver biopsy samples from 69 patients with chronic HCV infection and 19 uninfected individuals (controls) and measured levels of syndecan 1 (SDC1), SMAD7, and SMAD6 messenger RNAs (mRNAs). Small interfering RNA knockdown of SMAD6 blocked the binding and infection of hepatoma cell lines and primary human hepatocytes by HCV, whereas SMAD6 overexpression increased HCV infection. We found levels of mRNAs encoding heparan sulfate proteoglycans (HSPGs), particularly SDC1 mRNA, and cell surface levels of heparan sulfate to be reduced in cells after SMAD6 knockdown. SMAD6 knockdown also reduced transcription of genes encoding lipoprotein and cholesterol uptake receptors, including the LDL receptor (LDLR), the very LDLR, and the scavenger receptor class B member 1 in hepatocytes; knockdown of SMAD6 also inhibited cell uptake of cholesterol and lipoprotein. Overexpression of SMAD6 increased the expression of these genes. Similar effects were observed with knockdown and overexpression of SMAD7. In addition, HCV infection of cells increased

Effects of peach palm oil on performance, serum lipoproteins and haemostasis in broilers.

PubMed

Baldizán, G; Oviedo, M; Michelangeli, C; Vargas, R E

2010-12-01

1. An experiment was conducted to study the comparative effects of peach palm oil (PPO, Bactris gasipaes H.B.K), crude palm oil (CPO, Elaeis guinenesis), maize oil (MO) and beef tallow (BT) on serum total and lipoprotein cholesterol levels and haemostatic factors in broiler chickens. 2. Four experimental diets were formulated to be isocaloric (14·2 MJ AME(N)/kg) and isonitrogenous (230 g CP/kg). PPO was extracted from the whole dry fruit with hexane. Each fat was added to the diet in an amount equivalent to 25% of total dietary calories. Six replicate groups of eight male broiler chicks were assigned randomly to each dietary treatment. Diets were fed on ad libitum basis. The experiment lasted 42 d. 3. At 42 d, birds were fasted overnight and three chickens/dietary treatment were utilised to draw blood for lipoprotein separation. Various haemostatic factors were determined in thrombocyte-poor plasma. Thrombocyte aggregation was assayed in whole blood. 4. No significant differences were detected in body-weight gain or feed efficiency between the chickens fed on the PPO diet and those receiving the CPO, MO or BT diets. Total serum cholesterol (TC), very low density lipoprotein cholesterol and low density lipoprotein cholesterol (LDL(C)) were not significantly affected after consuming the PPO, CPO and MO diets. Serum high density lipoprotein cholesterol (HDL(C)) was reduced only by the MO diet. Birds fed on the PPO diet had a significantly lower [corrected] LDLC/HDLC ratio compared with other dietary treatments 5. Thrombocyte count and thrombin time were not significantly affected by the experimental diets. Dietary oils significantly affected prothrombin time, fibrinogen concentration and thrombocyte aggregation. PPO and MO diets elicited the lowest fibrinogen levels compared to the CPO and BT diets. Thrombocyte aggregation in broilers fed on the PPO diet was similar to that of the CPO, MO and BT diets. 6. The results suggest that PPO might efficiently provide up to

Superior short-term cholesterol control and achievement of the adult treatment panel III low-density lipoprotein goals with initiation of statin therapy by the time of hospital discharge following acute myocardial infarction.

PubMed

Bybee, Kevin A; Powell, Brian D; Williams, Brent A; Murphy, Joseph G; Kopecky, Stephen L; Wright, R Scott

2004-03-15

In a community-based population, we compared serum cholesterol concentrations following hospital discharge after acute myocardial infarction based on statin therapy at the time of hospital discharge. At the time of follow-up cholesterol measurement, patients discharged from the hospital on a statin had lower mean low-density lipoprotein (LDL) (106.4 vs 116.7 mg/dl, p <0.01) and total cholesterol (182.2 vs 193.6 mg/dl, p <0.01) concentrations, larger absolute reductions in LDL (-24.7 vs -4.7 mg/dl, p <0.01) and total cholesterol (-24.2 vs -0.1 mg/dl, p <0.01) from pre-myocardial infarction levels, and superior attainment of the Adult Treatment Panel III LDL goal of <100 mg/dl at the time of follow-up compared with patients who were discharged without a statin (49% vs 33%; adjusted odds ratio 2.56; p <0.01).

Self-Reported Snoring Is Associated with Dyslipidemia, High Total Cholesterol, and High Low-Density Lipoprotein Cholesterol in Obesity: A Cross-Sectional Study from a Rural Area of China.

PubMed

Zhang, Naijin; Chen, Yintao; Chen, Shuang; Jia, Pengyu; Guo, Xiaofan; Sun, Guozhe; Sun, Yingxian

2017-01-17

Studies to explore the relationship between self-reported snoring and dyslipidemia, especially high total cholesterol (TC) and high low-density lipoprotein cholesterol (LDL-C), in the general population are still lacking. Our study was designed to examine whether self-reported snoring is significantly associated with dyslipidemia and ascertain the effects of different snoring intensities on dyslipidemia. There were 10,139 participants in our study. After adjustment for all confounding factors, self-reported snoring (OR = 1.207; p = 0.003), moderate (OR = 1.229; p = 0.015), strong (OR = 1.222; p = 0.033), and very strong (OR = 1.467; p = 0.012) snoring intensity, but not low (OR = 1.110; p = 0.224) snoring intensity, were significantly associated with dyslipidemia among adults with BMI (body mass index) ≥ 25 kg/m². In addition, self-reported snoring was significantly associated with high TC (OR = 1.167; p = 0.048) and high LDL-C (OR = 1.228; p = 0.044), rather than low HDL-C (OR = 1.171; p = 0.057) and high triglyceride (TG) (OR = 1.110; p = 0.141). In conclusion, adults with BMI ≥ 25 kg/m² and who experience snoring, especially moderate, strong, and very strong intensity levels of snoring, should be on the alert regarding the possibility of dyslipidemia, especially high LDL-C and high TC.

Progression of Chronic Kidney Disease Affects HDL Impact on Lipoprotein Lipase (LPL)-Mediated VLDL Lipolysis Efficiency.

PubMed

Ćwiklińska, Agnieska; Cackowska, Monika; Wieczorek, Ewa; Król, Ewa; Kowalski, Robert; Kuchta, Agnieszka; Kortas-Stempak, Barbara; Gliwińska, Anna; Dąbkowski, Kamil; Zielińska, Justyna; Dębska-Ślizień, Alicja; Jankowski, Maciej

2018-06-15

Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency. VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated. HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased. The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and

G-protein estrogen receptor as a regulator of low-density lipoprotein cholesterol metabolism: cellular and population genetic studies.

PubMed

Hussain, Yasin; Ding, Qingming; Connelly, Philip W; Brunt, J Howard; Ban, Matthew R; McIntyre, Adam D; Huff, Murray W; Gros, Robert; Hegele, Robert A; Feldman, Ross D

2015-01-01

Estrogen deficiency is linked with increased low-density lipoprotein (LDL) cholesterol. The hormone receptor mediating this effect is unknown. G-protein estrogen receptor (GPER) is a recently recognized G-protein-coupled receptor that is activated by estrogens. We recently identified a common hypofunctional missense variant of GPER, namely P16L. However, the role of GPER in LDL metabolism is unknown. Therefore, we examined the association of the P16L genotype with plasma LDL cholesterol level. Furthermore, we studied the role of GPER in regulating expression of the LDL receptor and proprotein convertase subtilisin kexin type 9. Our discovery cohort was a genetically isolated population of Northern European descent, and our validation cohort consisted of normal, healthy women aged 18 to 56 years from London, Ontario. In addition, we examined the effect of GPER on the regulation of proprotein convertase subtilisin kexin type 9 and LDL receptor expression by the treatment with the GPER agonist, G1. In the discovery cohort, GPER P16L genotype was associated with a significant increase in LDL cholesterol (mean±SEM): 3.18±0.05, 3.25±0.08, and 4.25±0.33 mmol/L, respectively, in subjects with CC (homozygous for P16), CT (heterozygotes), and TT (homozygous for L16) genotypes (P<0.05). In the validation cohort (n=339), the GPER P16L genotype was associated with a similar increase in LDL cholesterol: 2.17±0.05, 2.34±0.06, and 2.42±0.16 mmol/L, respectively, in subjects with CC, CT, and TT genotypes (P<0.05). In the human hepatic carcinoma cell line, the GPER agonist, G1, mediated a concentration-dependent increase in LDL receptor expression, blocked by either pretreatment with the GPER antagonist G15 or by shRNA-mediated GPER downregulation. G1 also mediated a GPER- and concentration-dependent decrease in proprotein convertase subtilisin kexin type 9 expression. GPER activation upregulates LDL receptor expression, probably at least, in part, via proprotein convertase

The effect of cholesterol overload on mouse kidney and kidney-derived cells.

PubMed

Honzumi, Shoko; Takeuchi, Miho; Kurihara, Mizuki; Fujiyoshi, Masachika; Uchida, Masashi; Watanabe, Kenta; Suzuki, Takaaki; Ishii, Itsuko

2018-11-01

Dyslipidemia is one of the onset and risk factors of chronic kidney disease and renal function drop is seen in lipoprotein abnormal animal models. However, the detailed molecular mechanism of renal lipotoxicity has not been clarified. Therefore, the present study aimed to investigate the influence of cholesterol overload using mouse kidney tissue and kidney-derived cultured cells. C57BL/6 mice were fed normal diet (ND) or 1.25% cholesterol-containing high-cholesterol diet (HCD) for 11 weeks, and we used megalin as a proximal tubule marker for immunohistology. We added beta-very low density lipoprotein (βVLDL) to kidney-derived cells and examined the effect of cholesterol overload on megalin protein and mRNA expression level, cell proliferation and cholesterol content in cells. In the kidney of HCD mice, the gap between glomerulus and the surrounding Bowman's capsule decreased and the expression level of megalin decreased. After βVLDL treatment to the cells, the protein expression and mRNA expression level of megalin decreased and cell proliferation was restrained. We also observed an increase in cholesterol accumulation in the cell and free cholesterol/phospholipid ratios increased. These findings suggest that the increased cholesterol load on kidney contribute to the decrease of megalin and the overloaded cholesterol is taken into the renal tubule epithelial cells, causing suppression on cell proliferation, which may be the cause of kidney damage.

Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical outcomes.

PubMed

Clark, Donald; Nicholls, Stephen J; St John, Julie; Elshazly, Mohamed B; Kapadia, Samir R; Tuzcu, E Murat; Nissen, Steven E; Puri, Rishi

2018-04-21

Utilizing serial intravascular ultrasonography (IVUS), we aimed to exam the association of intra-individual lipid variability, coronary atheroma progression, and clinical outcomes. We performed a post hoc patient-level analysis of nine clinical trials involving 4976 patients with coronary artery disease who underwent serial coronary IVUS in the setting of a range of medical therapies. We assessed the associations between progression in percent atheroma volume (ΔPAV), clinical outcomes, and visit-to-visit lipid variability including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC)/HDL-C, and apolipoprotein B (ApoB). Variability of lipid parameters was measured using intra-individual standard deviation over 3, 6, 12, 18, and 24 months. Atherogenic lipoprotein variability significantly associated with ΔPAV [odds ratio (95% confidence interval; P-value), LDL-C: 1.09 (1.02, 1.17, P = 0.01); non-HDL-C: 1.10 (1.02, 1.18, P = 0.01); TC/HDL-C: 1.14 (1.06, 1.24, P = 0.001); ApoB: 1.13 (1.03, 1.24, P = 0.01)]. Survival curves revealed significant stepwise relationships between cumulative major adverse cardiovascular events and increasing quartiles of atherogenic lipoprotein variability at 24-months follow-up (log-rank P < 0.01 for all lipoproteins except HDL-C). Stronger associations were noted between achieved lipoprotein levels and ΔPAV [LDL-C: 1.27 (1.17, 1.39; P < 0.001); non-HDL-C: 1.32 (1.21, 1.45; P < 0.001); TC/HDL-C: 1.31 (1.19, 1.45; P < 0.001); ApoB: 1.20 (1.07, 1.35; P = 0.003)]. Greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and clinical outcomes, although the association between achieved atherogenic lipoproteins and atheroma progression appears stronger. These data highlight the importance of achieving low and consistent atherogenic lipoprotein levels to promote

CHOLESTEROL REQUIREMENT OF PRIMARY DIPLOID HUMAN FIBROBLASTS

PubMed Central

Holmes, Richard; Helms, Judy; Mercer, Gretchen

1969-01-01

Primary cultures of fibroblast-like cells were obtained from skin and articular cartilage of human donors in the age bracket of 1 to 15 years. For growth these cultures required 1 mg/liter of cholesterol added to Medium A2 plus acetyl choline, Na pyruvate, and D-galactosamine HCl (APG) containing 10% lipoprotein-free human serum. Established cell lines did not require cholesterol for growth. Eagle's medium could be used in place of Medium A2 plus APG with the same results. Desmosterol could replace cholesterol but lansterol or 7 dehydrocholesterol could not. Other cholesterol precursors were tested and found to be inactive. With the proviso that cholesterol precursors entered the cell and had to be converted to cholesterol to function, it was concluded that the particular primaries studied lacked a functional enzyme system to reduce the double bond at carbon 7. PMID:5786984

The Effects of Extended Release Niacin on Lipoprotein Sub-Particle Concentrations in HIV-Infected Patients

PubMed Central

Lin, Chunrong; Grandinetti, Andrew; Shikuma, Cecilia; Souza, Scott; Parikh, Nisha; Nakamoto, Beau; Kallianpur, Kalpana J

2013-01-01

With the advent of highly active antiretroviral therapy (HAART), Cardiovascular Disease (CVD) has emerged as the leading cause of death in Human Immunodeficiency Virus (HIV) infected patients. An atherogenic lipoprotein phenotype has been described in HIV- infected patients with a predominance of small, low density lipoprotein (SLDL) particles with accompanying elevated triglycerides and reduced high density lipoprotein cholesterol. This randomized controlled pilot study was conducted to evaluate the efficacy of Extended Release Niacin (ERN) in improving the lipid profile in HIV patients. A total of 17 HIV positive subjects on HAART therapy with High Density Lipoprotein Cholesterol (HDL) levels below 40mg/dl and Low Density Lipoprotein Cholesterol (LDL) below 130mg/dl were enrolled. Nine were randomized to be treated with ERN titrated from a starting level of 500mg/night and titrated to a level of 1500mg/night. Eight patients were assigned to the control arm. No placebo was used. Lipoprotein profiles of the subjects were analyzed at baseline and at the end of 12 weeks using Nuclear Magnetic Resonance (NMR) spectroscopy. At the end of 12 weeks, NMR spectroscopic analysis revealed a significant increase in overall LDL size (1.2% in ERN treated subjects vs 2.0% decrease in control patients, P=.04) and a decrease in small LDL particle concentration (17.0% in ERN treated subjects vs 21.4% increase in control patients, P=.03) in subjects receiving ERN as compared to those in the control group. Only 1 subject receiving ERN developed serious flushing which was attributed to an accidental overdose of the drug. This pilot study demonstrates that ERN therapy in HIV-infected patients with low HDL is safe and effective in improving the lipoprotein profile in these patients. PMID:23795312

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

Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.

PubMed

Seiki, Stephanie; Frishman, William H

2009-01-01

Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.

Effect of long-term physical activity on PCSK9, high- and low-density lipoprotein cholesterol, and lipoprotein(a) levels: a prospective observational trial

PubMed

Sponder, Michael; Campean, Ioana-Alexandra; Dalos, Daniel; Emich, Michael; Fritzer-Szekeres, Monika; Litschauer, Brigitte; Bergler-Klein, Jutta; Graf, Senta; Strametz-Juranek, Jeanette

2017-08-09

INTRODUCTION    Since proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were introduced to the market, the interest in PCSK9 metabolism has increased dramatically. OBJECTIVES    We investigated prospectively the influence of long-term physical activity on PCSK9, highand low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively), and lipoprotein(a) levels [Lp(a)]. PATIENTS AND METHODS    A total of 109 participants were recruited and instructed to increase their sport pensum by 75 min/wk of vigorous-intensity or 150 min/wk of moderate-intensity endurance training (or a mixture) within the calculated training pulse for 8 months. Stress tests were performed at baseline and at the end of the study to prove and quantify the performance gain. PCSK9 levels were measured at baseline and after 2, 6, and 8 months by an enzyme-linked immunosorbent assay. HDL-C, LDL-C, and Lp(a) levels were measured at baseline and every 2 months. RESULTS    The final study sample included 79 subjects, who showed a mean performance gain of 11.4%. Mean (SD) PCSK9 and HDL-C levels increased significantly from 224.7 (66.8) ng/ml to 243.4 (84.0) ng/ml (P = 0.04) and 58.3 (18.4) mg/dl to 61.1 (18.5) mg/dl (P = 0.014), respectively. Mean (SD) LDL-C levels decreased significantly from 115.0 (33.4) mg/dl to 109.8 (31.7) mg/dl (P = 0.04), but there was no significant change in mean (SD) Lp(a) levels: 37.9 (51.9) nmol/l to 43.3 (60.6) nmol/l; P = 0.218. CONCLUSIONS    Our study showed a decrease in LDL-C levels induced by a long-term physical activity with a simultaneous increase in PCSK9 levels. PCSK9 is essential in lipid metabolism and should not be basically considered as harmful. It is possible that a certain amount of PCSK9 is beneficial to ensure an adequate lipid supply.

Cardiovascular Disease, Mortality Risk and Healthcare Costs by Lipoprotein(a) Levels According to Low Density Lipoprotein-Cholesterol Levels in Older High Risk Adults

PubMed Central

Zhao, Yanglu; Delaney, Joseph A; Quek, Ruben G.W.; Gardin, Julius M.; Hirsch, Calvin; Gandra, Shravanthi R.; Wong, Nathan D.

2017-01-01

Background The value of lipoprotein(a) [Lp(a)] for predicting cardiovascular disease (CVD) across low density lipoprotein-cholesterol (LDL-C) is uncertain. We examined in older high risk adults these associations with CVD events, mortality, and healthcare costs. Methods We included 3,251 high risk subjects (prior CVD, diabetes or 10-year Framingham CVD risk > 20%) aged ≥ 65 years from the Cardiovascular Health Study with LDL-C and Lp(a). We examined the relation of Lp(a) tertiles with incident CVD, coronary heart disease (CHD) and all-cause mortality within LDL-C strata (< 70 mg/dL, 70–99 mg/dL, 100–129 mg/dL, 130–159 mg/dL and ≥ 160 mg/dL). We also examined 1-year all-cause and CVD healthcare costs from Medicare claims. Results Over up a 22.5-year follow-up, higher Lp(a) levels predicted CVD and total mortality [both standardized hazard ratio (HR) =1.06, p<0.01] while higher LDL-C levels predicted higher CHD (standardized HR =1.09, p<0.01) but lower total mortality (standardized HR =0.94, p< 0.001). Adjusted HRs in the highest (vs. lowest) tertile of Lp(a) level were 1.95 (p=0.06) for CVD events and 2.68 (p=0.03) for CHD events when LDL-C was < 70 mg/dL. One year all-cause healthcare costs were increased for Lp(a) [$771 per SD of 56 ug/mL (p=0.03), $1,976 for Lp(a) 25–64 ug/mL vs. < 25 ug/mL (p=0.02) and $1648 for Lp(a) ≥ 65 ug/mL vs. < 25 ug/mL (p=0.054)], but not LDL-C. Conclusion In older high risk adults, increased Lp(a) levels were associated with higher CVD risk especially in those with LDL-C < 70 mg/dL and with higher healthcare costs. PMID:27177347

The triglyceride-to-high density lipoprotein cholesterol ratio in overweight Korean children and adolescents.

PubMed

Yoo, Dong-Yoon; Kang, Yu Sun; Kwon, Eun Byul; Yoo, Eun-Gyong

2017-09-01

The triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio has recently been reported as a biomarker of cardiometabolic risk in obese children and adolescents. The purpose of this study is to describe the TG/HDL-C ratio and related factors in overweight and normal weight Korean children and to evaluate whether the high TG/HDL-C ratio is associated with insulin resistance in overweight children and adolescents. Data from 255 overweight (aged 8.7±2.0 years) and 514 normal weight (aged 8.9±1.8 years) children and adolescents were evaluated. Glucose, insulin, total cholesterol (TC), HDL-C and TG levels were measured after overnight fasting, and the TG/HDL-C ratio, non-HDL-C and the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. The TG/HDL-C ratio was higher in overweight group compared to normal weight group (P<0.001). Among overweight children and adolescents, alanine aminotransferase (P=0.018), non-HDL-C (P<0.001), and HOMA-IR (P=0.004) were different between the TG/HDL-C ratio tertile groups. The prevalence of elevated HOMA-IR was increased with increasing TG/HDL-C ratio tertiles (P for trend=0.003). On regression analysis adjusted for age and sex, the BMI (β=0.402, P=0.001) and TG/HDL-C ratio (β=0.251, P=0.014) were independently associated with HOMA-IR (adjusted R2=0.324). The TG/HDL-C ratio of 2.0 or more showed higher sensitivity (55.6%) and specificity (72.9%), when compared to TC (≥200 mg/dL), non-HDL-C (≥145 mg/dL), and LDL-C (≥130 mg/dL) for identifying overweight children with elevated HOMA-IR. The TG/HDL-C ratio is independently associated with insulin resistance in overweight children and adolescents, and it can be useful in identifying those at higher cardiometabolic risk.

The triglyceride-to-high density lipoprotein cholesterol ratio in overweight Korean children and adolescents

PubMed Central

Yoo, Dong-Yoon; Kang, Yu Sun; Kwon, Eun Byul

2017-01-01

Purpose The triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio has recently been reported as a biomarker of cardiometabolic risk in obese children and adolescents. The purpose of this study is to describe the TG/HDL-C ratio and related factors in overweight and normal weight Korean children and to evaluate whether the high TG/HDL-C ratio is associated with insulin resistance in overweight children and adolescents. Methods Data from 255 overweight (aged 8.7±2.0 years) and 514 normal weight (aged 8.9±1.8 years) children and adolescents were evaluated. Glucose, insulin, total cholesterol (TC), HDL-C and TG levels were measured after overnight fasting, and the TG/HDL-C ratio, non–HDL-C and the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Results The TG/HDL-C ratio was higher in overweight group compared to normal weight group (P<0.001). Among overweight children and adolescents, alanine aminotransferase (P=0.018), non–HDL-C (P<0.001), and HOMA-IR (P=0.004) were different between the TG/HDL-C ratio tertile groups. The prevalence of elevated HOMA-IR was increased with increasing TG/HDL-C ratio tertiles (P for trend=0.003). On regression analysis adjusted for age and sex, the BMI (β=0.402, P=0.001) and TG/HDL-C ratio (β=0.251, P=0.014) were independently associated with HOMA-IR (adjusted R2=0.324). The TG/HDL-C ratio of 2.0 or more showed higher sensitivity (55.6%) and specificity (72.9%), when compared to TC (≥200 mg/dL), non–HDL-C (≥145 mg/dL), and LDL-C (≥130 mg/dL) for identifying overweight children with elevated HOMA-IR. Conclusions The TG/HDL-C ratio is independently associated with insulin resistance in overweight children and adolescents, and it can be useful in identifying those at higher cardiometabolic risk. PMID:29025201

Optimal Serum Cholesterol Concentrations are Associated with Accelerated Bone Loss in African Ancestry Men

PubMed Central

Kuipers, Allison L.; Miljkovic, Iva; Evans, Rhobert; Bunker, Clareann H.; Patrick, Alan L.; Zmuda, Joseph M.

2016-01-01

Purpose Studies of lipid and lipoprotein cholesterol associations with bone mineral density (BMD) and bone loss have been inconclusive, and longitudinal data are sparse. Therefore, the aim of this study was to test if fasting serum lipid and lipoprotein cholesterol levels are associated with areal and volumetric BMD and BMD change, Methods We determined the association of serum triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol concentrations with cross-sectional and longitudinal (mean follow-up: 6.1 years) measures of BMD in a cohort of 1289 in African ancestry men (mean age: 56.4 years). Fasting serum triglycerides, HDL and LDL were measured at baseline concurrent with BMD assessments. Dual-energy X-ray absorptiometry was used to quantify integral hip BMD and peripheral quantitative computed tomography at the radius and tibia was used to quantify volumetric BMD. Men were categorized as optimal, borderline or high-risk for triglyceride, HDL and LDL concentrations based on adult treatment panel III guidelines. Results Lower serum triglyceride or LDL and higher HDL concentrations were associated with lower trabecular BMD at baseline (all p<0.05). Similarly, men classified as having optimal levels of LDL, HDL or triglycerides at baseline experienced the greatest integral BMD loss at the hip and trabecular BMD loss at the tibia (all p<0.05), independent of potential confounding factors. Conclusions We found that clinically optimal serum lipid and lipoprotein cholesterol concentrations were associated with accelerated bone loss among Afro-Caribbean men. Further studies are needed to better understand the mechanisms involved and potential clinical significance of these findings. PMID:26602914

Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members

PubMed Central

MacArthur, Jennifer M.; Bishop, Joseph R.; Stanford, Kristin I.; Wang, Lianchun; Bensadoun, André; Witztum, Joseph L.; Esko, Jeffrey D.

2007-01-01

We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles. PMID:17200715

Reference Values for The Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Non-High-Density Lipoprotein Cholesterol in Korean Children and Adolescents: The Korean National Health and Nutrition Examination Surveys 2007–2013

PubMed Central

Shim, Young Suk; Baek, Joon Woo; Kang, Min Jae; Oh, Yeon Jeong; Yang, Seung

2016-01-01

Aim: Cholesterol levels vary throughout childhood and adolescence. The aim of the present study was to evaluate and identify age- and gender-specific reference values for serum lipid concentrations including non-high-density lipoprotein cholesterol (non-HDL-C) and the triglyceride to HDL-C ratio (TG/HDL-C ratio) in apparently healthy Korean children and adolescents. Methods: A total of 6197 participants aged 10 to 19 years old from the 2007–2013 Korean National Health and Nutrition Examination Survey were analyzed. Serum lipid concentrations were evaluated according to age and gender. Results: The overall mean concentration of non-HDL-C was 105.5 ± 25.6 mg/dL, with a significant gender difference: 103.3 ± 26.1 mg/dL in boys and 107.9 ± 24.7 mg/dL in girls (p = 0.028). The median values of non-HDL-C concentrations in boys and girls, respectively, were 111 and 112 mg/dL in the 10-year-old age group, 95 and 103 mg/dL in the 15-year-old age group, and 109 and 103 mg/dL in the 19-year-old age group. The overall mean TG/HDL-C ratio was 1.74 ± 1.22, and there were no significant gender differences: 1.77 ± 1.25 in boys and 1.72 ± 1.22 in girls (p = 0.183). The median values of the TG/HDL-C ratio in boys and girls were 1.16 and 1.00 in the 10-year-olds, 1.54 and 0.95 in the 15-year-olds, and 1.74 and 0.84 in the 19-year-olds, respectively. Conclusions: Age- and gender-specific reference values for non-HDL-C and for the TG/HDL-C ratio in children and adolescents could provide valuable information for individualized interpretations of lipid profiles and interventions as well as for strategies to prevent and manage childhood and adolescent dyslipidemia. PMID:27373984

Effects of soy bean on serum paraoxonase 1 activity and lipoproteins in hyperlipidemic postmenopausal women.

PubMed

Shidfar, Farzad; Ehramphosh, Elham; Heydari, Iraj; Haghighi, Ladan; Hosseini, Sharieh; Shidfar, Shahrzad

2009-05-01

Because of an unfavorable serum lipoprotein profile, postmenopausal women are at risk of cardiovascular disease. Soy protein may help protect against these risk factors, although its effect on paraoxonase 1 (PON1) is not clear. The aim of the present study was to determine the effects of soy protein on serum concentration of lipoproteins and PON1 activity in hypercholesterolemic postmenopausal women. In a double-blind randomized clinical trial with a parallel design, 52 hypercholesterolemic postmenopausal women were randomly assigned to 50 g/day soy protein containing 164 mg isoflavones or placebo, for 10 weeks. Serum lipoproteins and PON1 activity were measured at baseline and at the 10th week. There was significant increase in PON1 activity (P=0.029) and a significant decrease in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), LDL-C/high-density lipoprotein cholesterol (HDL-C), triacylglycerol/HDL-C and TC/HDL-C in the soy group compared with the placebo group (P=0.001, P=0.008, P=0.012, P=0.04 and P=0.029, respectively) at the end of the study. Similarly, PON1 activity was significantly increased (P=0.015) and LDL-C, TC, LDL-C/HDL-C, triacylglycerol/HDL-C and TC/HDL-C were significantly decreased (P=0.001, P=0.002, P=0.001, P=0.016 and P=0.001) at the end of the study compared with the beginning value in soy group. Soy protein reduces the cardiovascular disease risk in postmenopausal women because of both modest reductions in serum lipoproteins and an increase in PON1 activity.

Cholesterol and Triglycerides in Antipsychotic-Naive Patients with Nonaffective Psychosis

PubMed Central

Kirkpatrick, Brian; Garcia-Rizo, Clemente; Tang, Kun; Fernandez-Egea, Emilio; Bernardo, Miguel

2010-01-01

Patients with psychosis have an increased prevalence of hyperlipidemia. We compared fasting concentrations of lipids in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis (N-87) and control subjects (N=92). After accounting for gender, age, smoking, socioeconomic status, and body mass index, there was no significant difference between the two groups in total cholesterol, high-density lipoproteins, low-density lipoproteins, or triglycerides. PMID:20576293

Association of height and pubertal timing with lipoprotein subclass profile: exploring the role of genetic and environmental effects.

PubMed

Jelenkovic, Aline; Bogl, Leonie H; Rose, Richard J; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kaprio, Jaakko; Silventoinen, Karri

2013-01-01

Little is known about the relationship between growth and lipoprotein profile. We aimed to analyze common genetic and environmental factors in the association of height from late childhood to adulthood and pubertal timing with serum lipid and lipoprotein subclass profile. A longitudinal cohort of Finnish twin pairs (FinnTwin12) was analyzed using self-reported height at 11-12, 14, 17 years and measured stature at adult age (21-24 years). Data were available for 719 individual twins including 298 complete pairs. Serum lipids and lipoprotein subclasses were measured by proton nuclear magnetic resonance spectroscopy. Multivariate variance component models for twin data were fitted. Cholesky decomposition was used to partition the phenotypic covariation among traits into additive genetic and unique environmental correlations. In men, the strongest associations for both adult height and puberty were observed with total cholesterol, low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, and low-density lipoprotein particle subclasses (max. r = -0.19). In women, the magnitude of the correlations was weaker (max. r = -0.13). Few associations were detected between height during adolescence and adult lipid profile. Early onset of puberty was related to an adverse lipid profile, but delayed pubertal development in girls was associated with an unfavorable profile, as well. All associations were mediated mainly by additive genetic factors, but unique environmental effects cannot be disregarded. Early puberty and shorter adult height relate to higher concentrations of atherogenic lipids and lipoprotein particles in early adulthood. Common genetic effects behind these phenotypes substantially contribute to the observed associations. Copyright © 2013 Wiley Periodicals, Inc.

Effect of relative weight group change on nuclear magnetic resonance spectroscopy derived lipoprotein particle size and concentrations among adolescents.

PubMed

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

2014-05-01

To examine whether longitudinal changes in relative weight category (as indicated by change in body mass index [BMI] classification group) were associated with changes in nuclear magnetic resonance (NMR)-derived lipoprotein particles among US youth. Secondary analysis of data from a clustered randomized controlled trial. BMI and fasting blood samples were obtained from 2069 participants at the start of the 6th grade and end of the 8th grade. BMI was categorized as normal weight, overweight, or obese at both time points. Lipoprotein particle profiles were measured with NMR spectroscopy at both time points. Regression models were used to examine changes in relative weight group and change in lipoprotein variables. A total of 38% of participants changed relative weight category (BMI group) during the 2.5-year study period. Low-density lipoprotein (LDL) cholesterol and non-high-density lipoprotein (HDL) cholesterol decreased almost universally, but more with improved BMI category. There were adverse effects on LDL size and total LDL particles, HDL size, and cholesterol for participants who remained obese or whose relative weight group worsened. Changes in relative category had no impact on HDL particles. Improvement in relative weight group from 6th to 8th grade was associated with favorable changes in non-HDL cholesterol, very low-density lipoprotein size, LDL size, HDL size, and LDL particles but had no effect on HDL particles. Findings indicate that an improvement in relative weight group between 6th and 8th grade had an effect on NMR-derived particles sizes and concentrations among a large group of adolescents, which overrepresented low-income minorities. Copyright © 2014 Elsevier Inc. All rights reserved.

LDL-cholesterol Predicts a First CHD Event in Senior Citizens, Especially So in Those With Elevated Lipoprotein(a): Dubbo Study of the Elderly.

PubMed

Simons, Leon A; Simons, Judith; Friedlander, Yechiel; McCallum, John

2018-03-01

The analysis was designed to explore the combined effects of LDL-cholesterol and lipoprotein(a) (Lp(a)) in predicting incident coronary heart disease (CHD) in senior citizens without prior CHD. This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988-1989. Subjects with prior CHD (n=607) were excluded from this analysis. Incident CHD events were identified by hospital record linkage. The contributions of LDL and Lp(a) to CHD events and their combined effects were evaluated in proportional hazards regression models. There were 689 CHD events over 16 years in a cohort of 2198 men and women without prior CHD. LDL-cholesterol (corrected for cholesterol content of Lp(a)) and Lp(a) modelled in quartile categories each independently predicted CHD, but exclusively in Quartile 4 (Q4) for each parameter. Using the combination of LDL Q1 and Lp(a) Q1 as a reference group, LDL Q4 (>4.90mmol/L) most clearly predicted CHD in combination with Lp(a) Q4 (>276mg/L), hazard ratio 1.95 (95%CI 1.31-2.90). The present findings may have important practical implications in clinical management. If Lp(a) is assessed in senior citizens without prior CHD and found to be genuinely low, elevated LDL-cholesterol may not require active intervention. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Dietary Tuna Dark Muscle Protein Attenuates Hepatic Steatosis and Increases Serum High-Density Lipoprotein Cholesterol in Obese Type-2 Diabetic/Obese KK-Ay Mice.

PubMed

Maeda, Hayato; Hosomi, Ryota; Fukuda, Mari; Ikeda, Yuki; Yoshida, Munehiro; Fukunaga, Kenji

2017-05-01

Tuna muscle consists of light and dark muscle in approximately equal proportions. However, besides for the light muscle of tuna, cod, sardine, and salmon, few researches have assessed the health-promoting functions of fish protein. Therefore, we evaluated the mechanisms underlying the alteration of lipid storage and cholesterol metabolism following the intake of tuna dark muscle protein (TDMP) by obese type-2 diabetic/obese mice. Four-week-old male KK-A y mice were separated into 2 dietary groups, with one group receiving a casein-based diet and the other receiving a diet with the substitution of part of the protein (50%, w/w) by TDMP (TDMP diet) for 4 wk. The TDMP diet significantly increased the content of serum high-density lipoprotein cholesterol, partly due to the reduction of the expression of scavenger receptor class B member 1 in epididymal white adipose tissue. In addition, dietary TDMP decreased the content of hepatic triacylglycerol, which could be due to the enhancement of carnitine palmitoyltransferase-2 activity through the activation of the expression of the peroxisome proliferative activated receptor-α in the liver. These results suggest that TDMP could have the potential to prevent the development of obesity-related diseases by suppressing the storage of hepatic triacylglycerol and cholesterol. © 2017 Institute of Food Technologists®.

Alpinumisoflavone and abyssinone V 4'-methylether derived from Erythrina lysistemon (Fabaceae) promote HDL-cholesterol synthesis and prevent cholesterol gallstone formation in ovariectomized rats.

PubMed

Mvondo, Marie A; Njamen, Dieudonné; Kretzschmar, Georg; Imma Bader, Manuela; Tanee Fomum, Stephen; Wandji, Jean; Vollmer, Günter

2015-07-01

Erythrina lysistemon was found to improve lipid profile in ovariectomized rats. Alpinumisoflavone (AIF) and abyssinone V 4'-methylether (AME) derived from this plant induced analogous effects on lipid profile and decreased atherogenic risks. To highlight the molecular mechanism of action of these natural products, we evaluated their effects on the expression of some estrogen-sensitive genes associated with cholesterol synthesis (Esr1 and Apoa1) and cholesterol clearance (Ldlr, Scarb1 and Cyp7a1). Ovariectomized rats were subcutaneously treated for three consecutive days with either compound at the daily dose of 0.1, 1 and 10 mg/kg body weight (BW). Animals were sacrificed thereafter and their liver was collected. The mRNA of genes of interest was analysed by quantitative real-time polymerase chain reaction. Both compounds downregulated the mRNA expression of Esr1, a gene associated with cholesterogenesis and cholesterol gallstone formation. AME leaned the Apoa1/Scarb1 balance in favour of Apoa1, an effect promoting high-density lipoprotein (HDL)-cholesterol formation. It also upregulated the mRNA expression of Ldlr at 1 mg/kg/BW per day (25%) and 10 mg/kg/BW per day (133.17%), an effect favouring the clearance of low-density lipoprotein (LDL)-cholesterol. Both compounds may also promote the conversion of cholesterol into bile acids as they upregulated Cyp7a1 mRNA expression. AIF and AME atheroprotective effects may result from their ability to upregulate mechanisms promoting HDL-cholesterol and bile acid formation. © 2015 Royal Pharmaceutical Society.

Red grape seed extract improves lipid profiles and decreases oxidized low-density lipoprotein in patients with mild hyperlipidemia.

PubMed

Razavi, Seyed-Mostafa; Gholamin, Sharareh; Eskandari, Ali; Mohsenian, Nakta; Ghorbanihaghjo, Amir; Delazar, Abbas; Rashtchizadeh, Nadereh; Keshtkar-Jahromi, Maryam; Argani, Hassan

2013-03-01

Hyperlipidemia can lead to atherosclerosis by lipoprotein deposition inside the vessel wall and oxidative stress induction that leads to the formation of atherosclerotic plaque. Oxidized low-density lipoprotein particles (Ox-LDL) have a key role in the pathogenesis of atherosclerosis. The lipid-lowering properties and antioxidants of the grape seed can be beneficial in atherosclerosis prevention. We conducted a randomized double-blind placebo-controlled crossover clinical trial. Fifty-two mildly hyperlipidemic individuals were divided into two groups that received either 200 mg/day of the red grape seed extract (RGSE) or placebo for 8 weeks. After an 8-week washout period, the groups were crossed over for another 8 weeks. Lipid profiles and Ox-LDL were measured at the beginning and the end of each phase. RGSE consumption reduced total cholesterol (-10.68±26.76 mg/dL, P=.015), LDL cholesterol (-9.66±23.92 mg/dL, P=.014), and Ox-LDL (-5.47±12.12 mg/dL, P=.008). While triglyceride and very low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased by RGSE, the changes were not statistically significant. RGSE consumption decreases Ox-LDL and has beneficial effects on lipid profile-consequently decreasing the risk of atherosclerosis and cardiovascular disorders-in mild hyperlipidemic individuals.

Ocimum basilicum ethanolic extract decreases cholesterol synthesis and lipid accumulation in human macrophages.

PubMed

Bravo, Elena; Amrani, Souliman; Aziz, Mohammed; Harnafi, Hicham; Napolitano, Mariarosaria

2008-12-01

Macrophage lipid accumulation induced by low density lipoproteins (LDL) plays a pivotal role in atherosclerotic plaque development. Previous work showed that Ocimum basilicum extract, used as hypocholesterolemic agent by traditional medicine in Morocco, has hypolipidemic activity in rat acute hyperlipimidemia. This study investigated the effects of ethanolic extract of O. basilicum on lipid accumulation in human macrophages. As modification of LDL increase atherogenicity of the particles we evaluated the effects of the extract on LDL oxidation. The extract caused a dose-related increase of LDL-resistance to Cu(2+)-induced oxidation. Furthermore, at the dose of 60 microg/ml, significantly decreases the accumulation of macrophage lipid droplets induced by modified LDL evaluated as by red-oil staining. Cholesterol esterification and triacylglycerol synthesis in the cells were not affected. Macrophage treatment with 60 microg/ml, but not 20 microg/ml, of the extract reduced newly synthesized unesterified cholesterol by about 60% and decreased scavenger receptors activity by about 20-30%, evaluated by the internalization of cholesterol carried by [(3)H]CE-aggregated-LDL. The results suggest that O. basilicum ethanolic extract has the capability to reduce foam cell formation through the reduction of cholesterol synthesis and the modulation of the activity of surface scavenger receptors.

Impact of avocado-enriched diets on plasma lipoproteins: A meta-analysis.

PubMed

Peou, Sokunthea; Milliard-Hasting, Brittany; Shah, Sachin A

2016-01-01

Optimizing plasma lipoproteins is the primary goal of pharmacotherapy and diet interventions in people at risk for cardiovascular diseases. Avocados offer a rich source of monounsaturated fat and may pose beneficial effects on the lipid profile. We aimed to perform a meta-analysis of randomized clinical trials assessing the impact of avocados on TC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and/or triglycerides (TG). We searched PUBMED, Cumulative Index to Nursing and Allied Health Literature, Index to Nursing and Allied Health Literature, and the Cochrane Database of Systemic Reviews from their inception to February 2015. The weighted mean difference from baseline was calculated for all endpoints. Subgroup analyses were performed to assess heterogeneity, and funnel plots inspected to assess publication bias. Ten unique studies (n = 229) were included. Avocado consumption significantly reduced TC, LDL-C, and TG by -18.80 mg/dL (95% confidence interval [CI], -24.56 to -13.05; I(2), 46.9%), -16.50 mg/dL (95% CI, -22.91 to -10.10; I(2), 72.5%), -27.20 mg/dL (95% CI, -44.41 to -9.99; I(2), 91.1%) respectively. High-density lipoprotein cholesterol decreased nonsignificantly by -0.18 mg/dL (95% CI, -3.23 to 2.88; I(2), 84.8%). Avocado-substituted diets significantly decrease TC, LDL-C, and TG levels. Substituting dietary fats with avocados versus adding to the free diet should be the primary recommendation strategy. Larger trials looking at the impact of avocados on major adverse cardiovascular events are warranted. Copyright © 2016 National Lipid Association. All rights reserved.

Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a)

PubMed Central