Associations Between Macronutrients From Different Dietary Sources and Serum Lipids in 24 639 UK Biobank Study Participants.

[Figure: see text].

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. METHODS: We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. RESULTS: The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. CONCLUSIONS: The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

[Are treatments with statins that are considered unsuitable really unsuitable?]. / ¿Son realmente inadecuados los tratamientos con estatinas considerados como inadecuados?

In the Catalonian Institute of health there are 2 well-established circumstances for indicating lipid-lowering drug treatment with statins in the primary prevention of ischaemic heart disease. These are, severe hypercholesterolaemia, with a low density lipoprotein cholesterol equal to or greater than 240mg/dL, or above 130mg/dL when the coronary risk is equal to or greater than 10% at 10 years. There are data that suggest that these 2 criteria are not the only ones used in routine clinical practice, as such that the majority of patients to whom it is indicated, do not meet either of these 2 conditions. This study aims to determine the characteristics of the patients when statins are indicated outside the aforementioned circumstances. It is concluded that around 40% of patients have clinical characteristics that could justify the treatment. The level of suitability could not be established in about 33% of the patients, due to not being able to determine the coronary risk.

Meta-analysis methods and models with applications in evaluation of cholesterol-lowering drugs.

In this paper, we propose a class of multivariate random effects models allowing for the inclusion of study-level covariates to carry out meta-analyses. As existing algorithms for computing maximum likelihood estimates often converge poorly or may not converge at all when the random effects are multi-dimensional, we develop an efficient expectation-maximization algorithm for fitting multi-dimensional random effects regression models. In addition, we also develop a new methodology for carrying out variable selection with study-level covariates. We examine the performance of the proposed methodology via a simulation study. We apply the proposed methodology to analyze metadata from 26 studies involving statins as a monotherapy and in combination with ezetimibe. In particular, we compare the low-density lipoprotein cholesterol-lowering efficacy of monotherapy and combination therapy on two patient populations (naïve and non-naïve patients to statin monotherapy at baseline), controlling for aggregate covariates. The proposed methodology is quite general and can be applied in any meta-analysis setting for a wide range of scientific applications and therefore offers new analytic methods of clinical importance.

Consuming a diet complying with front-of-pack label criteria may reduce cholesterol levels: a modeling study.

BACKGROUND/OBJECTIVES: Front-of-pack nutrition labels can help consumers to make healthier choices and stimulate healthier product development. This is the first modeling study to investigate the potential impact on cholesterol levels of consuming a diet consisting of products that comply with the criteria for a 'healthier choice logo'. SUBJECTS/METHODS: National food consumption and food composition data were used to estimate the nutrient intake of the Dutch adult population (18-70 years) before and after replacing foods that did not comply with the choices front-of-pack label criteria. Different scenarios were established. The difference in cholesterol levels in the Dutch population was assessed before and after replacement by means of equations from meta-analyses that calculate how blood lipids change when diet composition changes. RESULTS: After replacing non-complying products with products, which comply with the label's criteria (maximum scenario), saturated fatty acids median intake reduced from 14.5 to 9.8 en%. Trans-fatty acids reduced from 0.95 to 0.57 en%. The average predicted changes in low-density lipoprotein and total cholesterol levels were -0.25 and -0.31 mmol/l, respectively. Because high-density lipoprotein (HDL) cholesterol levels reduced as well (-0.05 mmol/l), overall, the result was a slightly positive change in the total cholesterol/HDL ratio (-0.03). CONCLUSIONS: Our findings suggest that the consumption of foods complying with the criteria for a front-of-pack label could contribute moderately to cardiovascular risk reduction via influencing blood lipids. These findings were independent of other potential effects on related health outcomes.

Long time evolution of atherosclerotic plaques.

The evolution of atherosclerosis in general, and the influence of wall shear stress on the growth of atherosclerotic plaques in particular, is an intricate phenomenon which is still only partly understood. We therefore propose a qualitative mathematical model which consists of a number of ordinary differential equations for the concentrations of the most relevant constituents of the atherosclerotic plaque. These equations were studied both for the case that the wall shear stress is a parameter (model A), and for the case in which the plaque evolution is coupled to the blood flow (model B) which results in a time dependent wall shear stress. We find that both models exhibit a class of marginally stable equilibria, all reflecting states in which the plaque only grows for a short period of time after a perturbation. The uncoupled model A, however, shows bi-stability between this class of equilibria and another equilibrium state in which the plaque experiences unlimited growth in time, if the LDL cholesterol intake exceeds a threshold value. In model B the bi-stability vanishes, but we find that there is still a critical value of the LDL cholesterol intake beyond which the lumen radius drastically decreases. We show that this decrease is quite sensitive to the value of the wall shear stress.

Comparative effects of high and low-dose simvastatin on prostate epithelial cells: the role of LDL.

Epidemiological studies have linked statin use with a decreased risk of advanced prostate cancer and an improved recurrence-free survival after radical therapy. It is unclear, however, whether statins could have direct effects against prostate cancer in a clinical setting, as their growth-inhibiting effects on prostate cancer cells have been demonstrated at drug concentrations which exceed the level in plasma during standard clinical dosing. We compared responses to high-dose and therapeutic-dose simvastatin in normal and cancerous prostate epithelial cells. Simvastatin was more effective at inhibiting the growth of normal prostate epithelial cells than of cancer cells. At therapeutic 100 nM concentration simvastatin had a cytostatic effect on normal cells: apoptosis was only slightly induced, but a decrease in cell cycle activity and an increase in senescence were observed. At therapeutic concentrations, lipophilic simvastatin caused a stronger growth inhibition than did hydrophilic rosuvastatin. In contrast, 10 µM simvastatin had a cytotoxic effect both on normal and cancer cells. Addition of LDL-cholesterol effectively reversed the cytostatic effect in all cell lines, but overcoming the cytotoxicity of 10 µM simvastatin required a combination of LDL-cholesterol and mevalonate. As LDL-cholesterol completely prevented the growth-inhibiting effect of therapeutic-dose simvastatin already at low, subphysiological concentrations it is unlikely that statins have direct effects on growth of prostate epithelial cells in vivo. Statins' possible benefits against prostate cancer could be due to systemic cholesterol-lowering, as suggested by epidemiological studies. Future clinical studies evaluating the effects of statins on prostate cancer prevention should monitor serum LDL and should probably administer statins at higher concentrations than those currently used in the treatment of hypercholesterolemia.

Resistance training changes LDL metabolism in normolipidemic subjects: a study with a nanoemulsion mimetic of LDL.

OBJECTIVE: To evaluate the effects of resistance training (RT) on the metabolism of an LDL-like nanoemulsion and on lipid transfer to HDL, an important step of HDL metabolism. METHODS: LDL-like nanoemulsion plasma kinetics was studied in 15 healthy men under regular RT for 1-4 years (age = 25 ± 5 years, VO(2)peak = 50 ± 6 mL/kg/min) and in 15 healthy sedentary men (28 ± 7 years, VO(2)peak = 35 ± 9 mL/kg/min). LDL-like nanoemulsion labeled with (14)C-cholesteryl-ester and (3)H-free-cholesterol was injected intravenously, plasma samples were collected over 24-h to determine decay curves and fractional clearance rates (FCR). Lipid transfer to HDL was determined in vitro by incubating of plasma samples with nanoemulsions (lipid donors) labeled with radioactive free-cholesterol, cholesteryl-ester, triacylglycerols and phospholipids. HDL size, paraoxonase-1 activity and oxidized LDL levels were also determined. RESULTS: The two groups showed similar LDL and HDL-cholesterol and triacylglycerols, but oxidized LDL was lower in RT (30 ± 9 vs. 61 ± 19 U/L, p = 0.0005). In RT, the nanoemulsion (14)C-cholesteryl-ester was removed twice as fast than in sedentary individuals (FCR: 0.068 ± 0.023 vs. 0.037 ± 0.028, p = 0.002), as well as (3)H-free-cholesterol (0.041 ± 0.025 vs. 0.022 ± 0.023, p = 0.04). While both nanoemulsion labels were removed at the same rate in sedentary individuals, RT (3)H-free-cholesterol was removed slower than (14)C-cholesteryl-ester (p = 0.005). HDL size, paraoxonase 1 and the transfer rates to HDL of the four lipids were the same in both groups. CONCLUSIONS: RT accelerated the clearance of LDL-like nanoemulsion, which probably accounts for the oxidized LDL levels reduction in RT. RT also changed the balance of free and esterified cholesterol FCR's. However, RT had no effect on HDL metabolism related parameters.

Exercise training accelerates the removal from plasma of LDL-like nanoemulsion in moderately hypercholesterolemic subjects.

OBJECTIVE: Exercise training improves plasma lipid profile and diminishes risk of coronary heart disease. Previously, we showed that training increases LDL plasma clearance, as tested by an artificial LDL-like nanoemulsion method, presumably by increasing LDL receptor activity. In this study, we investigated whether training could also improve LDL clearance in hypercholesterolemic subjects (HCh) that are exposed to increased risk of cardiovascular events. METHODS: Twenty sedentary HCh and 20 normolipidemic (NL) sedentary volunteers were divided into four groups: 12 HCh submitted to 4-month training program, 8 HCh with no exercise program, 12 NL submitted to 4-month training and 8 NL with no exercise program. An LDL-like nanoemulsion labeled with (14)C-cholesteryl ester was injected intravenously into all subjects and plasma samples were collected during 24 h after injection to determine the fractional clearance rate (FCR, in h(-1)) by compartmental analysis. The study was performed on the first and on the last day of the 4-month study period. RESULTS: In both, trained HCh and NL groups, training increased nanoemulsion FCR by 36% (0.0443+/-0.0126; 0.0602+/-0.0187, p=0.0187 and 0.0503+/-0.0203; 0.0686+/-0.0216, p=0.0827, respectively). After training, LDL cholesterol diminished in both HCh and NL groups. In HCh, but not in NL group, LDL susceptibility to oxidation decreased, but oxidized LDL was unchanged. In both non-trained groups FCR was the same for the last and the 4-month previous evaluation. CONCLUSION: In HCh, exercise training increased the removal of LDL as tested by the nanoemulsion, and this probably accounted for decreased LDL cholesterol and diminished LDL susceptibility to oxidation.

Cholesterol, LDL, and 25-hydroxycholesterol regulate expression of the steroidogenic acute regulatory protein in microvascular endothelial cell line (bEnd.3).

The steroidogenic acute regulatory (StAR) protein promotes intramitochondrial delivery of cholesterol to the cholesterol side-chain cleavage system. In this experiment, we first demonstrated that StAR expressed in endothelial cells as well. Immunochemistry showed positive staining of StAR in endothelial cells. To investigate whether steroids and oxysterols regulate StAR expression in endothelial cells, mouse brain microvascular endothelial cell line (bEnd.3) was treated with various steroids and oxysterols, including free cholesterol (CHO), low density lipoprotein (LDL), and 25-hydroxycholesterol (25-OH). All these three compounds increased StAR mRNA and protein expression in a time- and dose-dependent manner. When treated with CHO and LDL, the StAR mRNA change was prior to the protein change, suggesting that transcription may be one of the mechanisms of CHO and LDL regulation. In contrast to CHO and LDL, 25-OH increased StAR protein levels independently of mRNA amount. It suggested that 25-OH might regulate StAR activity at post-transcriptional level.

Dexamethasone impairs cholesterol egress from a localized lipoprotein depot in vivo.

Plasma high density lipoproteins play a central role in the prevention and regression of atherosclerosis, as they are known to promote egress of cholesterol from cells. Glucocorticoids increase plasma HDL, but enhance esterification of cholesterol in macrophages in vitro. A novel model to measure cholesterol egress from a well defined depot in vivo was used currently to study the effect of dexamethasone on reverse cholesterol transport. Cationized LDL (cat LDL) (200 microg cholesterol) was injected into the rectus femoris muscle of mice and the egress of cholesterol was studied as a function of time. Daily subcutaneous injection of dexamethasone (1.25 microg) raised plasma HDL levels by 40-80%. In mice injected with cat LDL labeled with 3H-cholesterol, daily treatment with dexamethasone slowed the loss of labeled cholesterol from the depot. With dexamethasone, there was no removal of the mass of lipoprotein cholesterol up to 14 days after injection of cat LDL, while in the controls 75% of the exogenous cholesterol mass had been cleared from the depot. When the cat LDL had been labeled with 3H-cholesteryl ester (3H-CE), apparent hydrolysis of 3H-CE amounted to 46, 75 and 97% in controls, but only to 20, 48 and 65% in dexamethasone treated mice on days 4, 8 and 14, respectively. In addition, dexamethasone stimulated cholesterol re-esterification as evidenced by recovery of 80% of the retained cholesterol mass as CE. In experiments with cultured macrophages exposed to modified LDL, dexamethasone increased the amount of labeled cholesteryl ester by 50-75% as compared to controls. Histological examination of the rectus femoris muscle after injection of cat LDL showed that in dexamethasone treated mice cellular infiltration was sparser on day 4, but not on day 8, and persisted longer than in controls. In conclusion, dexamethasone treatment impeded cholesterol egress from a lipoprotein depot by: a) reduction of early inflow of mononuclear cells; b) partial inhibition of cholesteryl ester hydrolysis, and c) enhancement of cholesterol esterification. The latter effect did not permit cholesterol egress from the injected site even in the presence of high plasma HDL in dexamethasone treated mice.

Estimulación del riesgo lipídico por niveles de colesterol sérico total / Appretiations of lipidic risk by total serum cholesterol

En 186 adultos sanos de Tucumán incluídos en la base de datos del Estudio de Factores de Riesgo en la Argentina SAC'88, se clasificó al riesgo lipídico como: 1) normal: LDL100 mg/dl; 2) intermedio: LDL entre 100-150 mg/dl; 3) elevado: LDL >150mg/dl. Se distribuyó a la población de acuerdo a la colesterolemia como: <200,200-250,>250. Para discriminar la población normal se seleccionó la cifra <170. En cada grupo constituido se determinó la incidencia de la relación Col Tol/HDL anormal (ò 4,5). Existen una relación lineal entre concentraciones crecientes de colesterol total y los siguientes: 1) Incidencia de LDL a valores de riesgo lipídico elevado (coeficiente de 0,998); 2) incidencia en la población de un conciente Col Tol/HDL anormal (coeficiente de 0,999). Los incrementos en el LDL tienden a ser compensados por aumentos en HDL (p=0,05-0,10) pero tal compensación es ineficaz. En consecuencia, las cifras de colesterol total discriminan a la población con : 1) riesgo lipídico normal: colesterol <170 (especificidad 88,6 por ciento, sensibilidad 77,55); 2)riesgo lipídico elevado: colesterol >250 (especificidad 94,9 por ciento, sensibilidad 53,6 por ciento); 3) riesgo lipídico anormal: colesterol>200 (especificidad 98,2 por ciento, sensibilidad 73,3 por ciento), a valores de riesgo lipídico intermedio (35,8 por ciento) y elevado (62,4 por ciento)

Contribution of a risk factor clinic to lipid management in patients with coronary artery disease.

The progress of a cohort of 145 patients seen between June 1986 and June 1989 was reviewed. These patients had treatment prescribed by the clinic and had data recorded over serial visits; they allowed us to determine the contribution of the risk factor clinic. Eighty-six percent had coronary artery disease. Patients were given nutritional advice, partly in groups. In addition 61% were treated with drug therapy. Seventy-four percent had modified their diet before the clinic visit but only 32% received less than 30% of energy from fat; the number rose to 67% by discharge. Sixty-four percent had a body mass index of 25 or greater, falling to 53% at discharge. Mean total cholesterol of the 145 patients was 7.9, HDL cholesterol 1.06, and total:HDL cholesterol ratio 7.7 mmol/L. Changes with clinic management were: total cholesterol -19%, HDL cholesterol +11%, total:HDL cholesterol ratio -25%, LDL cholesterol -21%. Despite these changes, levels were less than optimal for patients with coronary arterial disease in at least 50% of patients at the time of discharge. Improved results can be achieved only with a more aggressive approach to drug therapy. Recent studies in patients with coronary disease provide strong support for such a change in management.

Cholesterol-rich LDL perfused at physiological LDL-cholesterol concentration induces platelet aggregation and PAF-acetylhydrolase activation.

The aim of this research was to perform an in vivo study on the relationships between lipid oxide (LP), platelet aggregation and PAF-acetylhydrolase in a model using perfusion of cholesterol-rich LDL media diluted to physiological LDL-cholesterol concentration. Normal rabbits were infused with LDL (d 1.025-1.063 g/ml) extracted from rabbits previously fed either with standard food (I-LDL group), 1% cholesterol food (II-LDL group) or 1% cholesterol plus probucol (IV-LDL group). CU2+ modified II-LDL was also infused (III-LDL group). After dilution as above, LP increased significantly in III- and II-LDL media. After perfusion, LP significantly increased in III- and II-LDL groups as compared to baseline values and to control. Compared to the I-LDL group, PAF-acetylhydrolase and platelet aggregation significantly increased in III- and II-LDL groups. These data indicate the property of cholesterol- rich LDL to activate PAF-acetylhydrolase and enhance platelet aggregation, even when perfused through a medium containing a physiological LDL-cholesterol concentration.