Since 2007, the year of their first widespread use, genome-wide association studies (GWAS) have become the “gold standard” for the detection of causal genes and polymorphisms in all fields of human medicine. Cardiovascular disease (CVD), one of the major causes of morbidity and mortality, is no except ion. The first GWAS focused on hypercholesterole mia and dyslipid emia as the major CVD determinants. GWAS confirm the importance of most of the previously identified genes (e.g. APOE, APOB, LDL-R) and recogni ze the importance of new genetic determinants (e.g. within the CILP2 or SORT1 gene clusters). Nevertheless, the results of GWAS still require confirmation by independent studies, as interethnic and interpopulation variability of SNP effects have been reported. We analy zed an association between eight variants within seven through GWAs detected loci and plasma lipid values in the Czech post -MONICA population sample (N= 2,559). We confirmed an association (all P<0.01) between plasma LDL-cholesterol values and variants within the CILP2 (rs16996148), SORT1 (rs646776), APOB (rs693), APOE (rs4420638) and LDL-R (rs6511720) genes in both males (N= 1,194) and females (N =1,368). In contrast, variants within the APOB (rs515135), PCSK9 (rs11206510) and HMGCoAR (rs12654264) genes did not significantly affect plasma lipid values in Czech males or females. Unweighted gene score values were linearly associated with LDL-cholesterol values both in males (P<0.0005) and females (P<0.00005). We confirmed the effects of some, but not all analyzed SNPs on LDL-cholesterol levels, reinforcing the necessity for replication studies of GWA-detected gene variants., J. A. Hubacek, V. Adamkova, V. Lanska, D. Dlouha., and Obsahuje bibliografii
It has been reported that the virulence of axenically cultivated Entamoeba histolytica increases following growth with cholesterol. The purpose of this study was to determine whether cholesterol would enhance the virulence of axenically cultivated Naegleria fowleri. Amoebae were cultivated in axenic medium with (100 pg/ml) or without cholesterol for 6 months and tested in mice for changes in virulence. After 6 months of continuous cultivation, N. fowleri grown with cholesterol was less virulent for mice than the same strain grown without cholesterol.
Cholesterol 7α-hydroxylase (CYP7A1), the key regulatory enzyme of bile acid synthesis, displays a pronounced diurnal variation. To better understand the regulation of CYP7A1 activity, three daylong examinations were carried out in 12 healthy men. The concentrations of 7α-hydroxycholest-4-en-3-one (C4), a surrogate marker of CYP7A1 activity, bile acids (BA), insulin, glucose, nonesterified fatty acids, triglycerides, and cholesterol were measured in serum in 90-min intervals from 7 AM till 10 PM. To lower and to increase BA concentration during the study, the subjects received cholestyramine and chenodeoxycholic acid (CDCA), respectively, in two examinations. No drug was used in the control examination. There was a pronounced diurnal variation of C4 concentration with a peak around 1 PM in most of the subjects. The area under the curve (AUC) of C4 concentration was five times higher and three times lower when subjects were treated with cholestyramine and CDCA, respectively. No relationship was found between AUC of C4 and AUC of BA concentration, but AUC of C4 correlated positively with that of insulin. Moreover, short-term treatment with cholestyramine resulted in about 10 % suppression of glycemia throughout the day. Our results suggest that insulin is involved in the regulation of diurnal variation of CYP7A1 activity in humans., J. Kovář ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
MicroRNAs (miRNAs) are a class of short non-coding regulatory RNA molecules which play an important role in intracellular communication and cell signaling and which influence cellular processes such as proliferation, differentiation, and cellular death. Over the past two decades, the crucial role of m icroRNAs in controlling tissue homeostasis and disease in cardiovascular systems has become widely recogni zed. By controlling the expression levels of their targets, several miRNAs have been shown to modulate the function of endothelial cells (miR-221/222 and -126), vascular smooth muscle cells (miR-143/145) and macrophages (miR-33, -758, and -26), thereby regulating the development and progression of atherosclerosis. The stability of miRNAs within the blood suggests that circulating miRNAs may function as important biomarkers of disease development and progression. Numerous circulating miRNAs have been found to be dysregulated in a wide variety of different disease states, including diabetes, cancer, and cardiovascular disease., D. Dlouhá, J. A. Hubáček., and Obsahuje bibliografii
Using non-cholesterol sterols investigation several authors postulated a hypothesis that in the metabolic syndrome cholesterol endogenous synthesis is increased and its absorption decreased. Our study is the first attempt to evaluate the direct relation of cholesterol metabolism to the principal pathogenetic phenomenon of the metabolic syndrome – namely to insulin resistance. We have measured insulin sensitivity by two methods – Quicki (Quantitative Sensitivity Check Index) and intravenous insulin tolerance test (Kitt) and 3 indirect markers - fasting insulin level, fasting C-peptide level and SHBG (sex hormone binding globulin). The investigation was performed in three groups of subjects with a different prevalence of insulin resistance: 72 non-diabetics with ischemic heart disease, 117 young blood donors and 63 type 2 diabetics on diet therapy only. Analyzing altogether 60 relationships – between four sterols (lathosterol, squalene, sitosterol and campesterol) and five markers of insulin resistance in three groups of subjects – we have found only six significant relations between cholesterol synthesis and absorption and insulin resistance in all groups of patients. Our results indicate that there exists a significant relationship between insulin sensitivity and indices of either increased cholesterol synthesis or decreased cholesterol absorption. Insulin resistance explains only a part of both abnormalities mentioned above., A. Šmahelová, R. Hypšler, T. Haas., and Obsahuje bibliografii a bibliografické odkazy
The Prague Hereditary Hypercholesterolemic (PHHC) rat is a model of hypercholesterolemia. In previous experiments, it was found to be completely resistant to the development of atherosclerosis. It was assumed that the reverse transport of cholesterol (RCT) might be the reason for this resistance. In this study, RCT was measured in vivo by cholesterol efflux from macrophages to plasma, using previously established methods for RCT in mice (Rader 2003), optimized for measurements in rats. Primary cell culture of macrophages was labeled with 14Ccholesterol and then injected intraperitoneally into rats. Plasma and feces were collected at 24 and 48 h. The plasma 14Ccholesterol levels at both 24 and 48 h were significantly higher in male PHHC rats compared to control Wistar rats. The PHHC rats excreted less 14C-cholesterol in feces in 24 and 48 h compared to Wistar rats. The largest pool of 14C-cholesterol was found in the adipose tissue of PHHC rats and in contrast lower levels of 14Ccholesterol were measured in the liver and muscle tissues of PHHC rats compared with Wistar rats. Increasing release of 14Ccholesterol efflux from macrophages demonstrates accelerated RTC and leads to prevention of atherogenesis in PHHC rats., M. Schmiedtova, M. Heczkova, J. Kovar, I. Kralova Lesna, R. Poledne., and Obsahuje bibliografii
Silymarin, a mixture of flavonolignans from medicinal plant Silybum marianum, is used in supportive treatment of liver diseases of different etiology due to its hepatoprotective activity, which is considered to involve antioxidative and the membrane stabilizing effects. The liver plays an important role in regulation of metabolism of plasma lipoproteins, and liver injury is often reflected as a secondary dyslipoproteinaemia, which may lead to the development of atherosclerosis, particularly when associated with hypercholesterolaemia. This review summarizes the experimental evidence indicating that silymarin-induced protection of liver functions may be of benefit with regard to liver lipid metabolism related to the regulation of plasma lipoproteins. Moreover, some data suggest that silymarin could have a direct effect on liver cholesterol metabolism by inhibiting cholesterol biosynthesis. It is proposed that silymarin deserves to be studied as a potential hypocholesterolaemic agent.
a1_Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently used drugs in the prevention of coronary artery disease due to their cholesterol- lowering activity. However, it is not exactly known whether these effects of statins or those independent of cholesterol decrease account for the protection ag ainst myocardial ischemia- reperfusion (I/R) injury. In this study, we investigated the effect of 5-day treatment with simvastatin (10 mg/kg) in Langendorff- perfused hearts of healthy control (C) and diabetic- hypercholesterolemic (D-H; strept ozotocin + high fat-cholesterol diet, 5 days) rats subjected to 30-min global ischemia followed by 40-min reperfusion for the examination of postischemic contractile dysfunction and reperfusion-induced ventricular arrhythmias or to 30-min (left anterior descending) coronary artery occlusion and 2-h reperfusion for the infarct size determination (IS; tetrazolium stai ning). Postischemic recovery of left ventricular developed pressu re (LVDP) in animals with D-H was improved by simvastatin therapy (62.7±18.2 % of preischemic values vs. 30.3±5.7 % in the untreated D-H; P<0.05), similar to the values in the simvastatin-treated C group, which were 2.5-fold higher than those in the untreated C group. No ventricular fibrillation occurred in the simvastatin-treated C and D-H animals during reperf usion. Likewise, simvastatin shortened the duration of ventri cular tachycardia (10.2±8.1 s and 57.8±29.3 s in C and D-H vs. 143.6±28.6 s and 159.3±44.3 s in untreated C and D-H, respectively, both P<0.05). The decreased arrhythmogenesis in the simvastatin-treated groups correlated with the limitation of IS (in % of risk area) by 66 % and 62 % in C and D-H groups, respectively. However, simvastatin treatment decreased plasma cholesterol levels neither in the D-H animals nor in C., a2_The results indicate that other effects of statins (independent of cholesterol lowering) are involved in the improvement of contractile recovery and attenuation of lethal I/R injury in both, healthy and diseased individuals., A. Adameová, A. Harčárová, J. Matejíková, D. Pancza, M. Kuželová, S. Čarnická, P. Švec, M. Barteková, J. Styk, T. Ravingerová., and Obsahuje bibliografii
It has been reported that the major function of the sterol regulatory element binding protein 2 (SREBP-2) is to activate preferentially cholesterol biosynthesis in liver and adipose tissue rather than fatty acid synthesis. In the current study, we analyzed the effects of overexpression of human dominantpositive SREBP-2 transgene under control of PEPCK promoter in the spontaneously hypertensive rat (SHR) on lipid and glucose metabolism. Transgenic overexpression of SREBP-2 was associated with significantly higher hepatic triglycerides (20.4±0.9 vs. 17.0±0.05 μmol/g, P<0.05) but not cholesterol (10.6±0.4 vs. 10.9±0.4 μmol/g) and decreased relative weight of epididymal fat pad (0.73±0.03 vs. 0.830.03, P<0.05). In addition, muscle triglyceride (15.8±3.7 vs. 8.5±1.2 μmol/g, P<0.001) and cholesterol (3.6±0.5 vs. 2.1±0.1 μmol/g, P<0.05) concentrations were significantly increased in transgenic rats when compared to SHR controls. Ectopic fat accumulation was associated with significantly increased serum glucose levels (6.4±0.1 vs. 5.9±0.1 mmol/l, P<0.005) and reduced insulin levels (1.78±0.33 vs. 2.73±0.37 nmol/l, P<0.05) in transgenic rats. These results provide evidence for important role of SREBP-2 in regulation of lipid and glucose metabolism., V. Landa, V. Zídek, P. Mlejnek, M. Šimáková, J. Šilhavý, J. Trnovská, L. Kazdová, M. Pravenec., and Obsahuje bibliografii
Biological membrane mimetics, such as liposomes, lipid bilayers and model membranes, are used in a broad range of scientific and technological applications due to the unique physical properties of these amphiphilic aggregates. They serve as platforms for studying soft matter physics of membranes and membrane dynamics, interactions of bilayers with drugs, and effects of various additives of environmental changes. State-of-the-art research takes advantage of the combination of the brilliance of X-ray scattering sources with peculiar properties of neutrons and the power of computer simulations. The advances in chemistry, and in particular the possibility of deuteration, enables improved experimental spatial resolution and the ability to pi-point labels within membranes. It is only a matter of time for many biological functions, which occur at the membrane interface, to be matched with the structural properties of these membranes., Článok referuje o zákonitostiach stavby lipidových membrán a ich interakciách s biologicky aktívnymi molekulami. Vplyv iónov nachádzajúcich sa v prirodzenom prostredí bunkovej membrány, anestetický efekt alkánov a účinok cholesterolu a melatonínu pri zabudovaní do membrány je diskutovaný najmä z pohľadu zmeny štruktúry lipidovej matrice membrány. Štruktúrne výsledky sú získané pomocou experimentálnych prístupov, pričom dôraz sa kladie na pokrok dosiahnutý v metódach využívajúcich moderné zdroje röntgenového žiarenia a neutrónov., Norbert Kučerka., and Obsahuje bibliografii