Marek Vecka

Background: Newly described component of the metabolic syndrome is the elevated synthesis of cholesterol accompanied with its decreased intestinal absorption. The aim of our study was to ascertain the incidence of genotypes and alleles of several candidate genes, which modulate insulin resistance and metabolism of lipids and to find their role in lipid, lipoprotein and cholesterol homeostasis. The concentrations of cholesterol precursors (lathosterol, desmosterol, respectively their rations to cholesterol) are related to the synthesis of cholesterol; concentrations of fytosterols (kampesterol, sitosterol, respectively their rations to cholesterol) are related to the intestinal absorption of cholesterol. Methods and results: 95 patients with metabolic syndrome (56 M/39 F) and 195 healthy persons (99 M/96 F) were included into the study. Beside the basic clinical and anthropometric data, parameters of glucose homeostasis, plasma concentration of lipids, ultracentrifugation separated lipoproteins, and conjugated diens in LDL were determined. Non-cholesterol sterols were estimated by capillary gas chromatography. Polymorphisms of apolipoprotein E, intestinal isoforms of fatty acids binding protein (Ala54Thr), microsomal transfer protein (-493G/T), and gamma-2 isoforms of peroxisomal proliferator activated receptor (Ala12Pro) were analysed by combination of methods of polymerase chain reaction and by determination of polymorphism of the length of restriction fragments. After adjustation to the age, patients with metabolic syndrome had higher BMI, body fat and lean body weight (all P < 0.001), waist circumference, systolic and diastolic blood pressure (all P < 0.01). At the same time they had higher levels of glucose, insulin (P < 0.001), C-peptide, CRP (P < 0.05), uric acid, conjugated diens in LDL and HOMA insulin resistance index (P < 0.001). After adjustation to the age, higher concentration of triglycerides (P < 0.001), apo B (P < 0.01), cholesterol and triglycerides in VLDL (both P < 0.001), triglycerides in LDL (P < 0.01) were found. Incidence of alleles and genotypes of studied polymorphisms did not differ in both groups. Cholesterol synthesis is modulated by the presence of metabolic syndrome and by sex; cholesterol resorption is modulated only by the presence of metabolic syndrome. Conclusions: In patients with metabolic syndrome we found higher synthesis and lower intestinal absorption of cholesterol. We did not confirm relation between alleles of studied polymorphisms and clinical and anthropometric parameters, neither relation of these alleles to lipid or lipoprotein levels, oxidation stress, inflammation, or parameters of synthesis and absorption of cholesterol.

The article summarizes the nature and causes of the insulin resistance, its relation to the metabolic syndrome, and to the cardiovascular diseases. Insulin resistance can be defined as a set of abnormal clinical symptoms accompanied by lower tissue sensitivity to insulin. Metabolic syndrome, whose major components are impairments of glucose homeostase, obesity, dyslipidemia and arterial hypertension, represents an important risk factor for the development of diabetes mellitus type 2 and for the development of cardiovascular diseases. Possible factors, which can influence those relations, e.g., chronic inflammations, endothelial dysfunction and oxidation stress are discussed. The primary aims for the positive influencing the metabolic syndrome is the prevention of the development of diabetes mellitus type 2 and that of cardiovascular diseases. To approach those goals, the use of non-pharmacologic means (diet, appropriate physical activity) and pharmacologic (treatment of dyslipidemia, namely by statins and fibrates; management of hypertension, specifically by angiotensin-converging enzyme inhibitors, by angiotensin-receptor blockers, by glitazoe administration and by antithrombotic treatment) can be recommended.

Background: Dysregulation of fatty acids (FA) seems to participate in the pathogenesis of disorders such as metabolic syndrome (MetS), cardiovascular diseases, or some cancers. Activities of enzymes FA desaturases and elongases [elongation of very long-chain fatty acid (ELOVL)] significantly influence FA profile in different body compartments. Although the impact of activities of desaturases on cardiometabolic diseases was broadly studied, relatively little attention was devoted to the role of elongases. Methods: Case-control study was carried out in 36 patients (18 men/18 women) with impaired fasting glycemia (IFG) without MetS and 36 age and gender-matched healthy controls. FA profiles in plasma phospholipids (PL) were assessed using gas chromatograph-flame ionization detector and indices of desaturase and elongase activities were calculated. Results: In the IFG group, we observed decreased estimated activities of ELOVL2 and ELOVL5, whereas higher estimated activities of elongase ELOVL6 were noted. IFG group was also characterized by altered composition of plasma PL FA, above all by lower percentage of cis-vaccenic acid (cVA; 18:1n-7) and of total polyunsaturated FA n-6, especially linoleic acid, and by higher proportion of stearic acid and gamma-linolenic acid. Concurrently, elevated estimated activities of desaturases delta-9-desaturase (D9D), D6D were found. Conclusions: Lower estimated activities of ELOVL2 and ELOVL5 with lowered proportion of PL cVA could be associated with disturbances of glucose homeostasis development and their corresponding indices could serve as biomarkers of such risk.

States associated with insulin resistance, as overweight/obesity, type 2 diabetes mellitus (DM2), cardiovascular diseases (CVD), some cancers and neuropsychiatric diseases are characterized with a decrease of long-chain polyunsaturated fatty acids (LC-PUFA) levels. Amounts of LC-PUFA depend on the exogenous intake of their precursors [linoleic (LA) and α-linolenic acid (ALA)] and by rate of their metabolism, which is influenced by activities of enzymes, such as Δ6-desaturase (D6D, FADS2), D5D, FADS1, elongases (Elovl2, -5, 6).Altered activities of D5D/D6D were described in plenty of diseases, e.g. neuropsychiatric (depressive disorders, bipolar disorder, dementia), metabolic (obesity, metabolic syndrome, DM2) and cardiovascular diseases (arterial hypertension, coronary heart disease), inflammatory states and allergy (Crohns disease, atopic eczema) or some malignancies. Similar results were obtained in studies dealing with the associations between genotypes/haplotypes of FADS1/FADS2 and above mentioned diseases, or interactions of dietary intake of LA and ALA on one hand and of the polymorphisms of minor allels of FADS1/FADS2, usually characterized by lower activities, on the other hand.The decrease of the desaturases activities leads to decreased concentrations of products with concomitant increased concentrations of substrates. Associations of some SNP FADS with coronary heart disease, concentrations of plasma lipids, oxidative stress, glucose homeostasis, and inflammatory reaction, were described. Experimental studies on animal models and occurrence of rare diseases, associated with missing or with marked fall activities of D5D/D6D emphasized the significance of desaturases for healthy development of organism as well as for pathogenesis of some disease.

Fatty acids are monocarboxylic acids with chain-length 2-36 carbon atoms and 0-6 double bonds. Their physico-chemical properties are reflected also in the compounds, where fatty acids represent an important component (phospholipids, triglycerides), as well as in higher organized structures (plasma membranes, lipoproteins). Fatty acids are synthesized from two-carbon precursors; their degradation by beta-oxidation is accompanied by energy-release. Fatty acids are classified with respect to double bonds into saturated, monounsaturated and polyunsaturated. Simple lipids are esters of fatty acids and organic alcohols - cholesterol, glycerol and sphingosine and their derivatives. Endogenous acids can be desaturated up to Delta9 position; desaturation to other position is possible only from exogenous (essential) acids [(linoleic (n-6 series) and alpha-linolenic (n-3 series)]. Circulating lipids (in form of lipoproteins) consist of cholesterol esters and triglycerides in nonpolar core and phosphatidylcholin and sphingomyelin in the polar envelope of lipoproteins. Nonesterified fatty acids (product of lipolysis and source for lipid synthesis) are bound to plasma albumin. Membrane lipids, which ensure membrane fluidity and other functions, consist of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and some other (minor) phospholipids.

Polyunsaturated fatty acids of n-3 family play an important role in the prevention of ischemic heart disease, as was shown in many epidemiological as well as intervention studies. These fatty acids are essential and human organism is fully dependent on their dietary intake from chloroplast of green plants and fat of aquatic animals. Cardioprotective action of these acids results from their complex effect (antiarrhytmic, antithrombotic, antiinflammatory, hypolipidemic etc.). These acids can, with the exception of glucose homeostasis, favourably influence individual components of the metabolic syndrome. Beneficial effects of n-3 polyunsaturated fatty acids are supposed also in chronic inflammatory and autoimmune diseases, psychiatric-neurological diseases and malignant tumours. In the case of rheumatoid arthritis, antiinflammatory effects of polyunsaturated fatty acids were proven. In general, favourable effects of the optimal income of n-3 polyunsaturated fatty acids can be explained by the influencing of cellular metabolic functions, incorporation into membrane phospholipids, modulation of enzymes and signal molecules as well as by direct impact on gene expression. Polyunsaturated fatty acids of n-3 family have high therapeutic potential, which results from the combined action on different levels of cell functions. In some diseases, their effect is nearly pharmacological - prevention of the sudden death and fatal myocardial infarction, treatment of hyper- and dyslipoproteinemias, suppression of the inflammatory activity in rheumatoid arthritis. In another group of diseases, they have supporting effect (prevention of the arterial hypertension in metabolic syndrome) and, finally, in the last one (psychiatric-neurological diseases and tumours), more data of defined clinical groups are necessary for final evaluation.

Aim: To identify the total content of trans fatty acid (TFA) isomers and C18:1 trans isomers in subcutaneous fat samples from persons with atherosclerosis of the coronary arteries, as an indicator of dietary exposure. Methods: Using capillary gas chromatography, the authors determined total content of TFA isomers and C18:1 trans isomers in the subcutaneous fat of 34 patients with ischemic heart disease who had undergone aortocoronary bypass surgery and in 46 patients with no sign of coronary disease. Results: On average, the total TFAs in cardiac patients were 2.88 ± 1.19% of all fatty acids, in noncardiac patients 2.56 ± 0.89%. However, the difference is not statistically significant. The average concentration of C18:1 trans in cardiac patients (2.31 ± 1.09%) was statistically significantly higher (p = 0.05) than in the noncardiac group (1.95 ± 0.77%). Conclusions: The results obtained indicate a lower TFA load in comparison with previous studies in other countries. A higher concentration of 18:1 TFAs in the subcutaneous fat of patients with coronary disease might be an impulse to correct the dietary habits of this very high-risk population.

Fatty acids play multiple roles in humans and other organisms. In triglycerides they are the source of metabolic energy, in adipose tissue they serve also as temperature and mechanical isolators, in the form of phospholipids they are structural components of membranes. Fatty acids originating from the sn-2 glycerol carbon of phosphatidylcholine can influence the activity of diglycerides as second messengers. Unsaturated FA with 18-20 carbon atoms are precursors of prostaglandins, leucotrienes and thromboxanes, which have a broad scale of regulatory properties and have autocrine as well as paracrine effects. Fatty acids are ligands of several nuclear receptors, which take part in the subcellular control of a number of metabolic pathways. Covalent modification of proteins by FA (acylation) enables FA incorporation into the membranes. Number of pathological stages is accompanied with changes in fatty acid composition, often expressed as decreased content of unsaturated and increased content of saturated fatty acids (e.g. dyslipidemia, malnutrition, inflammation and inherited diseases). Polyunsaturated fatty acids as dietary supplements are used in prevention and in the therapy of cardiovascular diseases and other metabolic disturbances.

When making prescriptions for total parenteral nutrition (TPN) it is necessary to take into consideration also substitution with calcium and phosphorus. Under some clinical conditions, or in certain groups of patients, it is necessary to supply these substances in high doses with a reduced volume, which due to mutual interactions may be problematic. This experimental paper therefore examined the compatibility of commercially available or individual preparations containing the compounds of calcium and phosphorus. These preparations were examined in a mixture with clinically employed solutions of amino acids or with solutions of glucose. The evaluation was performed by titration until the development of a visible precipitate and also by means of the pharmacopoeial method of evaluation of particles below the level of visibility. Hydrogen phosphate was found to possess a lower compatibility and stability in mixtures containing calcium salts in comparison with dihydrogen phosphate or organic phosphate. Nevertheless, no significant differences were found between dihydrogen phosphate and organic phosphate. The experiment confirmed a better stability of organic calcium salt versus the inorganic one only in the samples containing solutions of amino acids. Of the solutions of amino acids under study, the best stabilizing properties were found in the solutions intended for use in neonatology and paediatrics.

Profiles of fatty acids in lipid classes of plasma and ultracentrifugally separated lipoproteins were analyzed by capillary gas chromatography. Contribution of individual steps of the whole procedure was calculated on the basis of the multiple analyses. GC contributes to the overall error by the smallest part. Contribution of the extraction, thin-layer chromatography separation and methylation processes might be comparable. The

Although most of us are more or less familiar with the term "cholesterol", the world of sterols is far more complicated and interesting. Apart from cholesterol, many non-cholesterol sterols can be found in human plasma and these sterols serve many important functions in human organism. They are either derived from endogenous biosynthesis of cholesterol or they come from dietary sources (phytosterols). The sole cholesterol molecule is used for keeping our cell membranes fit, for signalization purposes as well as a precursor for bile acids and steroid hormones. The compounds prior to cholesterol in its biosynthetic pathway were identified as vitamin D3 precursor, meiosis activating sterols and nowadays it seems that they could play a role in cholesterol homeostasis. The sterols from ingested vegetable sources, the phytosterols, are expelled from enterocytes and thus indirectly help our gut in coping with abundant cholesterol in the lumen. Higher plants synthesize many phytosterols, but in marine organisms, we can find other innumerous sterol molecules. The diversity of sterol molecules produced and resistance of their tetracyclic core to enzymatic activities implies crucial importance of sterols during the ontogenesis of multicellular organisms. First oxygen appeared on the Earth app. 2.7 billion years ago and since that time, every new life form took the advantage of oxygen needed also for build-up of sterol molecules. The last decades changed our view to the sterol molecules on almost at all levels of their appearance in human body. In the gut, the absorption of sterols was proven to be protein dependent and the quest for the transporter was successful. The general concepts of intracellular homeostasis of cholesterol have been described including the covalent interaction unbelievable so far - cholesterol and a protein. The clinical importance of non-cholesterol sterols rises with the effort to discover underlying facts about the causes of atherosclerosis. The compound in question, cholesterol, seems to be involved, but it sounds not to be crucial per se. The fact that the accumulation of phytosterols in sitosterolemia enhances the probability of early atherosclerosis onset further supports the hypothesis about some sterol (or steroid) compound being responsible on the molecular level for triggering the pathobiochemical cascade of events leading to atherosclerosis. Understanding the processes taking place in the enterocyte during the absorption of sterols resulted in synthesis of selective inhibitors at the level of sterol translocation into the enterocyte, sterol esterification and chylomicron packing, which are in different phases of clinical testing. The studies in the last part of the monograph represent the clinical potential of the analyses of non-cholesterol sterols. In well-defined groups, these analytes enables us to assess the changes in the homeostasis of cholesterol, which can be reflected in the concentration of total cholesterol. Furthermore, the high concentrations of some plasma sterols could point to the inborn errors of cholesterol biosynthesis (Smith-Laemli-Opitz syndrome), transport (sitosterolemia) or metabolization (cerebrotendinous xanthomatosis). Some issues concerning the research on the non-cholesterol sterols still remain unanswered - it is not known why some of the enzymes of the cholesterol biosynthesis (seladin-1, sterol D14 reductase) have other functions, qualitative aspects of sterol absorption are not satisfactorily explained and exact reason for expulsion of phytosterols from human body is not clear. Nevertheless, the authors hope that the presented facts can broaden the reader's perspective about the area, which is usually hidden beneath the cholesterol molecule.

s / Atherosclerosis 263 (2017) e111ee282 e274 and investigated whether they were associated with Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) plasma levels in these patients compared to controls. Methods: PCSK9 level was measured by sandwich ELISA using recombinant human PCSK9 protein as standard. ApoCII, apoCIII, and apoE levels were carried out by the immunoturbidimetry method using specific antibodies (on Konelab 20XT from Thermofisher) in a Tunisian cohort with T2DM (n1⁄450) compared to an ageand sex-matched control group (n1⁄450). Both clinical and biochemical parameters were determined in all patients. Results: Plasma apoCII, apoCIII and apoE levels were significantly higher in T2DM patients compared to controls (P &lt; 0.0001). Remarkably, plasma apoE level was positively associated with PCSK9 levels in diabetic patients (r1⁄4 0.326; P 1⁄40.02). However, apoCII and apoCIII plasma levels were not correlated with PCSK9 plasma levels (NS). Conclusions: Plasma apoCII, apoCIII and apoE are significantly increased in T2DM patients. The most important clinical application of apolipoproteins measurements in plasma is the assessment of the risk of developing vascular complications in T2DM. ApoE level appears to be the best risk marker among measured apolipoproteins in combination with PCSK9 which can contribute to the installation of atherosclerosis and the development of macrovascular complications in T2DM. PO530. IS LIPOPROTEIN SUBFRACTION ANALYSIS IN PATIENTS IN CHRONIC HEMODIALYSIS REASONABLE? A PILOT STUDY Magdalena Dusejovska, Barbora Stankova, Marek Vecka, Magdal ena Mokrejsova, Ales Zak, Ivan Rychlík. 1 Fresenius Medical Care, Dialysis unit, Prague, Czech Republic; 4th Department of internal medicine 1st Faculty of medicine Charles University and General Teaching Hospital, Prague, Czech Republic; 3rd Faculty of medicine Charles University, Prague, Czech Republic Aim: In patients (pts) with end-stage renal disease, paradoxically inverse relationship of total cholesterol with total mortality exists. The research is now focused on the lipoprotein classes and subclasses and on the possible role of small dense LDL and small HDL particles on the atherogenesis. The aim of our study was to examine differences in individual lipoprotein classes and subclasses between chronic high volume hemodiafiltration (HD HDF) patients and healthy volunteers (CON). Methods: 60 pts on HD HDF for at least 12 months (PTS) and 60 CON were included into the study. PTS and CON groups were age-matched. Individual lipoprotein classes and their subclasses were analysed by Quantimetrix Lipoprint System. Results: Significantly decreased levels of total, HDL and LDL cholesterols and increased levels of triacylglycerols in PTS compared to CON were observed. Despite the decreased levels of HDL-C in PTS, the amount of large HDL particles was higher in PTS than in CON (p&lt;0.0001), in PTS, levels of intermediate (p1⁄40.03) and small HDL (p&lt;0.0001) particles were lowered. In PTS, increased levels of VLDL-C and IDL-C were found (p&lt;0.0001). No difference in amount of small dense LDL particles between groups was observed. Different distribution of cholesterol between VLDL and LDL particles in PTS and CON was found (p&lt;0.004). Conclusions: The results of our study show different, atherogenic, lipoprotein phenotype of PTS in comparison with CON. In accordance with our findings we are planning the extension of the PTS group and of observed markers. This study was supported by project PRVOUK-P25/LF1/2 and RVO 64165. PO531. PLASMA LIPOPROTEINS IN CHRONIC KIDNEY DISEASE: INCREASED BINDING TO ARTERIAL PROTEOGLYCANS PREDICTS CARDIOVASCULAR MORTALITY Pedrelli Matteo, Stenvinkel Peter, Minniti Mirko Enea, Kruss Emma, Dikkers Arne, Ebtehaj Sanam, Gomaraschi Monica, Barany Peter, Qureshi Abdul Rashid, Camejo German, Lindholm Bengt, € O€ orni Katariina, Tietge Uwe, Calabresi Laura, Hurt-Camejo Eva, Parini Paolo. Karolinska Institutet, Division of Clinical Chemistry, Department of Laboratory Medicine, Stockholm, Sweden; AstraZeneca, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, Gothemburg, Sweden; Karolinska Institutet, Division of Renal Medicine and Baxter Novum, Department of CLINTEC, Stockholm, Sweden; University of Groningen University, Department of Pediatrics, Medical Center Groningen, Gr€ oningen, The Netherlands; Universit a degli Studi di Milano, Centro Enrica Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy; Wihuri Research Institute, Atherosclerosis Research Laboratory, Helsinki, Finland; Karolinska Institutet, Metabolism Unit, Department of Medicine, Stockholm, Sweden Aim: To study the impact of CKD on lipoprotein composition, size and functionalities. Methods: Individuals naïve to dialysiswere studied. The exploratory-cohort consists of 39CKDpatients stage 4-5 (median eGFR: 7; (10th-90thpercentile 4-25)mL/min/1.73m2), and 19 controls with normal…

This study analyzes fatty acid (FA) composition in plasma lipids and erythrocyte phospholipids while comparing septic and non‐septic critically ill patients. The aim was to describe impacts of infection and the inflammatory process. Patients with severe sepsis (SP, n = 13); age‐, sex‐ and APACHE II score‐matched non‐septic critically ill with systemic inflammatory response syndrome (NSP, n = 13); and age‐/sex‐matched healthy controls (HC, n = 13) were included in a prospective case–control study during the first 24 h after admission to the intensive care unit. In both SP and NSP, lower n‐6 polyunsaturated FA (PUFA) accompanied by higher proportions of monounsaturated FA (MUFA) in plasma phospholipids (PPL) was observed relative to HC. MUFA proportion was negatively correlated with n‐6 PUFA, high density lipoprotein cholesterol (HDL‐C), and albumin. MUFA was positively correlated with C‐reactive protein (CRP), procalcitonin (PCT), interleukins (IL‐6, IL‐10), oxidized low density lipo...

Lipolysis in adipose tissue and balance between energy intake and expenditure are involved in the regulation of adipose tissue mass. Several recent findings suggest that alterations in the regulation of lipolysis and/or energy balance might contribute to the development of obesity. Hormone-sensitive lipase and uncoupling proteins play important role in regulation of lipolysis in adipose tissue as well as in the regulation of energy balance of various tissues. Mechanisms of the control of expression of genes coding synthesis of these proteins are poorly known. A brief overview of the present knowledge of the effects of nutritional intervention on the regulation of lipolysis in adipose tissue and on the expression of genes of hormone-sensitive lipase and that of uncoupling proteins is given in this article. Results of the authors&#39; studies on the effect of calorie restriction on gene expression in adipose tissue are presented.

Background: The aim of the study was to determine how addition of n-3 polyenic fatty acids (PUFA) to the present treatment with statin + fibrate combination in diabetic dyslipidemia effects plasma lipids and lipoproteins, LDL lipoperoxidation, glucose homeostasis, concentration of serum homocysteine and selected inflammation indicators. Methods and results: 24 patients with type 2 diabetes, who after the combined hypolipidemic treatment (pravastatin 20 mg + micronized fenofibrate 200 mg per day) cannot reach the recommended target values for long time, received for three consecutive months supplementation of 3,6 g PUFA n-3 per day or a placebo (olive oil). At the beginning of the study, after three months of PUFA supplementation and after another three months of placebo administration, concentrations of plasma lipids, composition of fatty acids, plasma phosphatidylcholine (PC), cholesterol esters (CE) and triglycerides (TG), concentration of tHcy, conjugated diens (CD) in LDL and selected inflammation indicators (IL-6, TNFalpha, VCAM-1) were determined. n-3 PUFA supplementation resulted in the significant decrease of tHcy concentration (-29%, P < 0.01) and TG (-28%, P < 0.05) in plasma. During the period of placebo administration, values returned to base line levels. CD concentration in LDL after n-3 PUFA increased by 15% (P < 0.15, not significant), meanwhile after the placebo containing oleic acid it decreased by 18% (P < 0.05). Conclusions: Our results show that n-3 PUFA supplementation together with statin + fibrate combination in DDL patients can significantly decrease the risk of cardiovascular diseases.

Elevated plasma concentration of apolipoprotein B-48 (apoB-48) is an independent risk factor of cardiovascular disease. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipogenic enzyme and a key regulator of fuel metabolism. The aim of this study was to analyse associations between clinical, biochemical, and genetic factors and different apoB-48 levels in subjects at increased cardiometabolic risk. We examined 220 subjects exhibiting at least one metabolic syndrome (MetS) component. In conjunction with basic clinical, anthropometric and laboratory measurements, we analysed various polymorphisms of stearoyl-CoA desaturase-1 (SCD1). Subjects were divided into two groups according to the median apoB-48 level: (1) high apoB-48 (≥ 7.9 mg/l, N = 112) and (2) low apoB-48 (&lt; 7.9 mg/l, N = 108). Neither group differed significantly in anthropometric measures. High plasma apoB-48 levels were associated with increased systolic blood pressure (+3 %; P &lt; 0.05), MetS prevalence (59.8 vs...

Pancreatic cancer (PC) ranks as the fourth cause of cancer-related deaths in the Czech Republic. Evidence exists that deregulation of fatty acid (FA) metabolism is connected with some malignancies; therefore, we decided to analyze FA profile in plasma lipid classes in patients with PC with relation to tumor staging, nutritional status, and survival. The study included 84 patients (47 males, 37 females) with PC and 68 controls (36 males, 32 females). FA patterns were analyzed in plasma lipid classes by gas-chromatography. We observed increased proportion of total monounsaturated FA (MUFA) in PC group in all plasma lipid classes. These changes were connected with increased Δ9-desaturase (SCD1) and Δ5-desaturase indices. Correlations of dihomo-γ-linolenic acid (DHGLA) with these variables were opposite. Longer survival of patients was connected with higher content of EPA, DHA, and with lower SCD1 index, respectively. Plasma phospholipid proportions of α-linolenic acid, DHGLA, EPA, and n-3 polyunsaturated fatty acids displayed negative trend with tumor staging. Plasma lipid FA pattern in PC patients resulted from decreased dietary fat intake and increased de novo synthesis of FA with transformation into MUFA. Changes in FA profile implicated some pathophysiological mechanisms responsible for disturbed FA metabolism in PC and importance of appropriate nutritional support.

Background: Depressive disorder is a serious illness with a high incidence, proxime accessit after anxiety disorders among the psychiatric diseases. It is accompanied by an increased risk of development of type 2 diabetes mellitus, cardiovascular disease, and by increased all-cause mortality. Recently published data have suggested that factors connected with the insulin resistance are at the background of this association. Methods and results: In this pilot study we have investigated parameters of lipid metabolism and glucose homeostasis in consecutively admitted patients suffering from depressive disorder (DD) (group of 42 people), in 57 patients with the metabolic syndrome (MetS) and in a control group of 49 apparently healthy persons (CON). Depressive patients did not differ from the control group by age or body mass index (BMI) value, but they had statistically significantly higher concentrations of serum insulin, C-peptide, glucose, triglycerides (TG), conjugated dienes in LDL particles (CD-LDL), higher value of microalbuminuria and of insulin resistance (HOMA-IR) index. They simultaneously had significantly lower value of the insulin sensitivity (QUICKI) index. In comparison with the MetS group the depressive patients were characterized by significantly lower both systolic and diastolic blood pressure, BMI , serum TG, apolipoprotein B, uric acid, C-peptide and by higher concentrations of apolipoprotein A-I and HDL-cholesterol. On the contrary, we have not found statistically significant differences between the DD and MetS groups in the concentrations of serum insulin, glucose, HOMA and QUICKI indices, in CD-LDL and MAU. Conclusions: In this pilot study, we have found in patients with depressive disorder certain features of metabolic syndrome, especially insulin resistance and oxidative stress.

In human organism, the administration of nicotinic acid (niacin) leads to two types of effects. Within the physiological range (approximately = 20 mg/day), niacin has a vitamin-like role as pellagra preventing factor. The pharmacological dosage (approximately 0,5-4,5 g/day) substantially influences the plasma lipid and lipoprotein concentrations: decreases VLDL and LDL concentrations, changes the profile of LDL subfractions towards the larger particles as well as particles with lower density; it also profoundly increases the concentration of HDL-C in consequence of elevated concentration of HDL2 subfraction. Niacin as the only hypolipidemic drug reduces the lipoprotein(a) concentration. The hypolipidemic mechanism of niacin is different from that of other hypolipidemic drugs. On the basis of clinically controlled trials (both interventional epidemiological and angiographical), which satisfy the criteria of evidence-based medicine, it is possible to conclude that niacin falls unambiguously into the class of hypolipidemic drugs with proven beneficial effect not only on cardiovascular mortality and morbidity, but also on total mortality. Therefore, niacin should have an indisputable role in the pharmacological control of dyslipidemias. With the respect of basic mechanism (inhibition of the lipolysis of adipose tissue) with subsequent decrease in the concentration of free fatty acids and their flux to liver, niacin fulfils the criteria for pathogenetic treatment of atherogenic dyslipidemia in metabolic syndrome. The prerequisite condition for the niacin treatment is the respect for serious adverse effects and possible health hazards of administration (skin flush, hepatotoxicity and deterioration of glucose homeostasis). Recently discovered extrahypolipidemic effects of niacin (antioxidative activity, facilitation of reverse cholesterol transport, activation of PPAR-gamma, antithrombotic effects) and the introduction of drug forms with sustained (extended resp.) release of active compound (that minimizes the adverse effects and administration hazards) form together the basis for firm statement that the derivatives of nicotinic acid should be introduced to the clinical practice in Czech Republic.

Background: It is difficult to achieve satisfactory decreases of both plasma LDL-cholesterol (LDL-C) and triglycerides (TG) and increase of HDL-C with only single statin or fibrate treatment of patients with mixed hyperlipoproteinaemias (HLP). Combination treatment with both statin and fibrate has been shown to enhance achieving of recommended targets in these patients with high-risk of coronary heart disease. On the other hand unpleasant side effects including myopathy and rhabdomyolysis were described in some cases after statin-fibrate combination therapy. Aim of the study was to evaluate efficacy and safety of long-term treatment of pravastatin + fenofibrate or simvastatin + ciprofibrate therapy in the high-risk group of patients with severe mixed hyperlipoproteinemia. Methods and results: A set of 86 patients (55 M/31 F) was followed for a period at least one year (median 3 years). These patients were randomly assigned to combination of pravastatin 20 mg + fenofibrate 200 mg (n = 46) (group A), or simvastatin 20 mg + ciprofibrate 100 mg (n = 40) (group B). We have observed significant reduction in plasma TC (22% in group A, 20% in group B), in LDL-C (36%, resp. 33%), reduction of TG (44%, resp. 46%), apo-B (35%, resp. 33%) whilst HDL-C significantly increased (18%, resp. 16%). Concomitantly we have seen significant decreases in uricaemia (14%, resp. 18%). No patient needed to stop treatment due to abnormalities in liver function tests. Levels of creatinkinase became non-significantly elevated (by 16%, resp. 13%). No patient exhibited myopathy or rhabdomyolysis. Conclusions: The long-term combined therapy with statin-fibrate (pravastatin 20 mg + fenofirbrate 200 mg, or simvastatin 20 mg + ciprofibrate 100 mg) in severe mixed HLP was safe and effectively improved plasma lipid and apolipoprotein levels. Both combinations seemed to be similarly efficient and safe.

The lipids constitute majority of dry weight of mature human brain. From lipids, 35% is comprised of PUFA with long chain (LC-PUFA), especially docosahexaenoic acid (DHA) of n-3 family and arachidonic acid (AA) of n-6 family. Humans are dependent on dietary intake of both AA and DHA. Interestingly, the dietary n-6/n-3 ratio increased considerably during last century. LC-PUFAs play numerous roles in the brain, including structural (forming the physico-chemical properties in the lipid bilayer of cellular membranes) and signaling ones. Moreover, they influence neurogenesis and neurotransmission within the nervous tissue. The metabolites of PUFA modulate immune and inflammatory processes in the brain, oxidative stress as well as its consequences. Of high importance is also their connection with several metabolic factors involved in the proper function of the brain and/or were discovered to play a role in the pathogenesis of neuropsychiatric diseases - melatonin, homocysteine, leptin, and adiponectin. This review gives short view of the metabolism and possible mechanisms of PUFA n-3 action in the brain, and their role in the pathogenesis of psychiatric diseases.

Obesity, diabetes mellitus type 2 and dyslipidemia, characterized by hypertriglyceridemia and low HDL-cholesterol levels, are risk factors for cholesterol gallstone disease. The common denominator of above-mentioned states is insulin resistance. Hypolipidemic treatment significantly influences not only the biliary lipid composition, but also other etiopathogenetic mechanisms of the disease. Three principal defects are involved in gallstone formation - cholesterol supersaturation, accelerated nucleation, and gallbladder dysmotility. The degree of cholesterol saturation in gallbladder bile is the most important predictor of cholesterol crystal formation. Cholesterol, lecithin and bile acids are the major components in bile. According to the molar ratios of the three main components, simple or mixed micelles, unstable unilamellar or multilamellar vesicles are formed in the bile. The cholesterol supersaturation of the gallbladder bile and cholesterol crystal formation from the unstable multilamellar vesicles initiates the onset of cholesterol cholelithiasis. The pool of unesterified cholesterol is the source for VLDL synthesis; together with HDL-cholesterol, it is also the source for cholesterol secretion into the bile. The main metabolic products of cholesterol degradation are bile acids, which are synthesized predominantly from LDL-cholesterol. The rate of the production of primary bile acids is principally regulated by cholesterol 7alpha-hydroxylase (CYP7A 1). The treatment of dyslipidemia with niacin and resins does not influence the saturation of bile with cholesterol or the incidence of cholelithiasis. The effects of ezetimibe in human patients with the respect of cholesterol cholelithiasis have not been published. The fibrate treatment is associated with increased cholesterol saturation of bile due to inhibition of CYP7A1 activity, enhanced flux of cholesterol via HDL and increased secretion of cholesterol into bile. The clinical studies describe cholesterol supersaturation in bile and increased frequency of cholelithiasis as well. The administration of pravastatin and simvastatin led to reduced cholesterol saturation indexes. The patients with endogenous hypertriglyceridemia and low HDL-cholesterol being administered with polyunsaturated fatty acids of n-3 family had decreased cholesterol concentration in bile. Other authors described beneficial effect of fish oil on the biliary cholesterol nucleation time, improvement of gallbladder sensitivity to cholecystokinin and the prevention of cholesterol gallstone formations caused by rapid weight loss.

The prevalence of metabolic syndrome as well as the occurrence of depressive disorder, which are both connected with increased risk of diabetes mellitus type 2 and cardiovascular diseases, is continually increasing worldwide. These disorders are interconnected at various levels; the genetic one seems to be promising. Contribution of genetic factors to the aetiopathogenesis of depressive disorder weighs within the range 40-50 %, whereas the genetic background for the manifestation of metabolic syndrome is more complicated. In this pilot study, we investigated the incidence of polymorphisms in several genes supposed to play a role in the development of both depressive disorder and metabolic syndrome such as brain-derived neurotrophic factor, methylenetetrahydrofolate reductase, tyrosine hydroxylase, and endothelial nitric oxide synthase. The entire group consisted of 42 patients with depressive disorder, 57 probands with metabolic syndrome and 41 control individuals. We found that genotype Met/Met of the Val66Met polymorphism of the brain-derived neurotrophic factor gene was positively associated with depressive disorder (P < 0.05), but we were not able to find any significant associations of both the depressive disorder and metabolic syndrome with the remaining polymorphisms studied (methylenetetrahydrofolate reductase 677CT, methylenetet rahydrofolate reductase 1298AC, endothelial nitric oxide synthase Glu298Asp, and tyrosine hydroxylase).

Background: Depressive disorder (DD) is associated with an increased risk of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). It was suggested, that metabolic syndrome (MetS), cluster of metabolic and hormonal changes, such as insulin resistence (IR), abdominal obesity, dyslipidemia, arterial hypertension and elevated fasting glycaemia, could stand behind the connection. Recent findings have shown, that adipocytokines leptin and adiponectin might play a role in both depression and MetS. Aim: The aim of this pilot study was to observe the plasma concentrations of leptin, adiponectin, leptin-to-adiponectin ratio and indices of IR in women with depressive disorder. Materials and methods: The plasma leptin, adiponectin, parameters of lipid and glucose homeostasis and indices of IR were investigated in a group of 38 women with DD. The results were compared with those of 38 healthy women of the control group, matched for age. Results: Depressive women differed significantly from the controls in higher concentrations of plasma leptin (p <0.05), insulin (p <0.01), C-peptide (p <0.01), value of HOMA-IR (p <0.01), and the leptin-to-adiponectin ratio (p <0.05).The QUICKI index of insulin sensitivity was lower (p <0.01). HAM-D score of DD cases correlated negatively with adiponectin (r = - 0.3505; p < 0.05), independently of HOMA-IR. We have not found in DD group any differences between the drug free patients and those treated either with escitaloprame alone or in the combination with mirtazapine. Conclusions: The results of the pilot study presented support the hypothesis that at least part of DD cases has increased leptin serum levels and certain features of MetS. It could be the factor connecting depression with an increased risk of either DM2 or CVD.

In human organism, the administration of nicotinic acid (niacin) leads to two types of effects. Within the physiological range (approximately = 20 mg/day), niacin has a vitamin-like role as pellagra preventing factor. The pharmacological dosage (approximately 0,5-4,5 g/day) substantially influences the plasma lipid and lipoprotein concentrations: decreases VLDL and LDL concentrations, changes the profile of LDL subfractions towards the larger particles as well as particles with lower density; it also profoundly increases the concentration of HDL-C in consequence of elevated concentration of HDL2 subfraction. Niacin as the only hypolipidemic drug reduces the lipoprotein(a) concentration. The hypolipidemic mechanism of niacin is different from that of other hypolipidemic drugs. On the basis of clinically controlled trials (both interventional epidemiological and angiographical), which satisfy the criteria of evidence-based medicine, it is possible to conclude that niacin falls unambiguously into the class of hypolipidemic drugs with proven beneficial effect not only on cardiovascular mortality and morbidity, but also on total mortality. Therefore, niacin should have an indisputable role in the pharmacological control of dyslipidemias. With the respect of basic mechanism (inhibition of the lipolysis of adipose tissue) with subsequent decrease in the concentration of free fatty acids and their flux to liver, niacin fulfils the criteria for pathogenetic treatment of atherogenic dyslipidemia in metabolic syndrome. The prerequisite condition for the niacin treatment is the respect for serious adverse effects and possible health hazards of administration (skin flush, hepatotoxicity and deterioration of glucose homeostasis). Recently discovered extrahypolipidemic effects of niacin (antioxidative activity, facilitation of reverse cholesterol transport, activation of PPAR-gamma, antithrombotic effects) and the introduction of drug forms with sustained (extended resp.) release of active compound (that minimizes the adverse effects and administration hazards) form together the basis for firm statement that the derivatives of nicotinic acid should be introduced to the clinical practice in Czech Republic.

Background: It is difficult to achieve satisfactory decreases of both plasma LDL-cholesterol (LDL-C) and triglycerides (TG) and increase of HDL-C with only single statin or fibrate treatment of patients with mixed hyperlipoproteinaemias (HLP). Combination treatment with both statin and fibrate has been shown to enhance achieving of recommended targets in these patients with high-risk of coronary heart disease. On the other hand unpleasant side effects including myopathy and rhabdomyolysis were described in some cases after statin-fibrate combination therapy. Aim of the study was to evaluate efficacy and safety of long-term treatment of pravastatin + fenofibrate or simvastatin + ciprofibrate therapy in the high-risk group of patients with severe mixed hyperlipoproteinemia. Methods and results: A set of 86 patients (55 M/31 F) was followed for a period at least one year (median 3 years). These patients were randomly assigned to combination of pravastatin 20 mg + fenofibrate 200 mg (n = 46) (group A), or simvastatin 20 mg + ciprofibrate 100 mg (n = 40) (group B). We have observed significant reduction in plasma TC (22% in group A, 20% in group B), in LDL-C (36%, resp. 33%), reduction of TG (44%, resp. 46%), apo-B (35%, resp. 33%) whilst HDL-C significantly increased (18%, resp. 16%). Concomitantly we have seen significant decreases in uricaemia (14%, resp. 18%). No patient needed to stop treatment due to abnormalities in liver function tests. Levels of creatinkinase became non-significantly elevated (by 16%, resp. 13%). No patient exhibited myopathy or rhabdomyolysis. Conclusions: The long-term combined therapy with statin-fibrate (pravastatin 20 mg + fenofirbrate 200 mg, or simvastatin 20 mg + ciprofibrate 100 mg) in severe mixed HLP was safe and effectively improved plasma lipid and apolipoprotein levels. Both combinations seemed to be similarly efficient and safe.

Obesity, diabetes mellitus type 2 and dyslipidemia, characterized by hypertriglyceridemia and low HDL-cholesterol levels, are risk factors for cholesterol gallstone disease. The common denominator of above-mentioned states is insulin resistance. Hypolipidemic treatment significantly influences not only the biliary lipid composition, but also other etiopathogenetic mechanisms of the disease. Three principal defects are involved in gallstone formation - cholesterol supersaturation, accelerated nucleation, and gallbladder dysmotility. The degree of cholesterol saturation in gallbladder bile is the most important predictor of cholesterol crystal formation. Cholesterol, lecithin and bile acids are the major components in bile. According to the molar ratios of the three main components, simple or mixed micelles, unstable unilamellar or multilamellar vesicles are formed in the bile. The cholesterol supersaturation of the gallbladder bile and cholesterol crystal formation from the unstable multilamellar vesicles initiates the onset of cholesterol cholelithiasis. The pool of unesterified cholesterol is the source for VLDL synthesis; together with HDL-cholesterol, it is also the source for cholesterol secretion into the bile. The main metabolic products of cholesterol degradation are bile acids, which are synthesized predominantly from LDL-cholesterol. The rate of the production of primary bile acids is principally regulated by cholesterol 7alpha-hydroxylase (CYP7A 1). The treatment of dyslipidemia with niacin and resins does not influence the saturation of bile with cholesterol or the incidence of cholelithiasis. The effects of ezetimibe in human patients with the respect of cholesterol cholelithiasis have not been published. The fibrate treatment is associated with increased cholesterol saturation of bile due to inhibition of CYP7A1 activity, enhanced flux of cholesterol via HDL and increased secretion of cholesterol into bile. The clinical studies describe cholesterol supersaturation in bile and increased frequency of cholelithiasis as well. The administration of pravastatin and simvastatin led to reduced cholesterol saturation indexes. The patients with endogenous hypertriglyceridemia and low HDL-cholesterol being administered with polyunsaturated fatty acids of n-3 family had decreased cholesterol concentration in bile. Other authors described beneficial effect of fish oil on the biliary cholesterol nucleation time, improvement of gallbladder sensitivity to cholecystokinin and the prevention of cholesterol gallstone formations caused by rapid weight loss.

BACKGROUND This study examines the associations of fatty acids (FAs) in plasma phosphatidylcholine (PC) with the anthropometrical and biochemical characteristic of patients with metabolic syndrome (MetS)-related traits. METHODS We analyzed the FA profiles of PC in 300 persons with MetS-related traits (152 M/148F, mean age 46.9 ± 9.0 years) and in 70 healthy controls of the same age using a balanced men/women ratio and gas-liquid chromatography. Multivariate linear regression analysis was performed to determine the coefficients of determination (R2) using FA proportions of the mentioned proband characteristics. RESULTS The FA composition of PC in patients with MetS traits was only associated with waist circumference (R2 = 0.27), waist-to-hip ratio (WHR; R2 = 0.41), body fat percentage (R2 = 0.62), and fat mass (R2 = 0.29). Positive associations were found for dihomo-γ-linolenic (DGLA), palmitic, stearic (SA), α-linolenic (ALA), and eicosapentaenoic acids, whereas negative associations were found for linoleic (LA), oleic, and docosapentaenoic acids. Palmitoleic acid (POA) was positively associated with waist circumference but negatively with fat percentage. In controls, significant associations were found for waist circumference (R2 = 0.51), WHR (R2 = 0.53), body fat percentage (R2 = 0.60), and fat mass (R2 = 0.34). DGLA and saturated FA (SFA) were positively associated, whereas docosahexaenoic, adrenic, and cis-vaccenic acids were negatively associated. The study group differed from controls as follows: lower concentrations of LA and total n-6 FA, higher indices of delta-9-desaturase and delta-6 desaturase activity and higher proportions of POA, SA, ALA, DGLA, and SFA. CONCLUSIONS We found significant associations (R2 &gt;0.25) of FA in plasma PC with adiposity in middle-aged persons with MetS-related traits, but not with metabolic indices.

The aim of this study was to study the effect of adding polyunsaturated fatty acid (PUFA) n-3 or placebo (containing oleic acid) to a combined statin-fibrate treatment on plasma lipoproteins, lipoperoxidation, glucose homeostasis, total homocysteine (tHcy) and microalbuminuria (MA) in patients with diabetic dyslipidemia (DDL). Twenty-four patients, who did not fulfill the recommended target lipid values with combined hypolipidemic therapy (pravastatin 20 mg+micronized fenofibrate 200 mg daily), were supplemented with 3.6 g PUFA n-3 daily for 3 months or placebo (olive oil) for the next 3 months. The concentrations of plasma lipids, fatty acid (FA) profiles of phosphatidylcholine (PC), cholesteryl esters (CE) and triglycerides (TG), tHcy levels, concentrations of conjugated dienes (CD) in low-density lipoprotein (LDL), and MA were determined in baseline state, after the PUFA n-3 and placebo treatment period. Supplementation with PUFA n-3 led to a significant decrease in plasma tHcy (-29%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) and TG (-28%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05) levels, as well as to a significant decrease in MA (-24%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). The decrease in MA correlated significantly with the increase in total PUFA n-3 (r = -.509, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = .05) and docosahexaenoic acid (r = -.52, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) in TG. The concentrations of CD in LDL increased significantly (+15%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). The supplementation with PUFA n-3 to the combined statin-fibrate treatment in patients with DDL decreased the TG and tHcy levels as well as MA. It could lead to decreased risk of atherothrombosis and delay of diabetic nephropathy onset and progression.

Vast knowledge has accumulated recently on the role of reactive oxygen and nitrogen species (RONS) in clinical medicine. Strong evidence was disclosed on their important role in the pathogenesis of several diseases. Free radicals have unpaired electron and this is the reason for extreme reactivity causing propagation reactions that lead to the multiple damage to cells. Oxidizing agents belong to the family of reactive species. Reactive oxygen species are produced during biochemical processes such as oxidative phosphorylation, phagocytosis and metabolism of purins. Overproduction of reactive oxygen species can cause the tissue damage. Reactive nitrogen species are produced by inhibition of nitric oxide synthase by the action of asymmetric dimethylarginine. Peroxisomal oxidases, NAD(P) oxidase, xanthinoxidase, nitric oxide synthase, myeloperoxidase and lipooxygenase catalyze biochemical reactions producing reactive oxygen and nitrogen species. Biochemical and molecular processes in cells are negatively influenced by chemical modification of DNA, proteins and lipids caused by the action of reactive oxygen and nitrogen species. Antioxidant metabolites and enzymes work together to stop and to prevent oxidative modification of biomolecules. Reactive oxygen and nitrogen species play an important role in the pathogenesis of many diseases such as atherosclerosis, diabetes, hyperlipidaemia and neurodegenerative diseases.