70 research outputs found
BOOK REVIEWS: The Metabolic and Molecular Basis of Acquired Disease Vols 1 and 2 by R.D. Cohen, B. Lewis, K.G.M.M. Alberti, A.M. Denman
No full textLipid and lipoprotein disorders
No full textLipids are a heterogeneous group of substances that are distinguished by their low solubility in water and their high solubility in nonpolar (organic) solvents. They are essential as energy stores and respiratory substrates, as structural components of cells, as vitamins, as hormones, for the protection of internal organs, for heat conservation, for digestion, and for lactation....</p
MOLECULAR CHARACTERIZATION OF TWO PATIENTS WITH SEVERE LCAT DEFICIENCY
No full textLecithin:cholesterol acyltransferase (LCAT; EC2.3.1.43) is the major enzyme responsible for theesterification of cholesterol in circulating plasmalipoproteins. This is important in the human becauseunlike many other animal species, cholesterol exportedinto the plasma from the liver is largely unesterified.LCAT associates in plasma preferentially with thediscoidal apo A-I containing high-density lipoproteins(preb1-HDL), where it esterifies the free cholesterol(FC) using apo A-I as co-factor [1]. Through thisaction, LCAT plays a central role in both HDLmaturation to a-migrating spherical HDL and inreverse transport of cholesterol from peripheral tissuesto the liver, directly by interaction of the mature HDLwith the hepatic SR-BI receptor, or indirectly bytransfer of CE by cholesteryl ester transfer protein(CETP) to the VLDL and then LDL, much of which isultimately cleared by the liver via the LDL receptor [2].In addition, LCAT protein seems to have a scavengereffect toward LDL oxidation products, which isindependent of its cholesterol-esterifying activity [3].Mutations of LCAT (chr. 16q22.1, 6 exons) inhomozygous or compound heterozygous form cancause two major phenotypes: FLD (familial LCATdeficiency) and FED (Fish Eye Disease). Patients withFLD (OMIM No, 245900) have a complete loss ofboth a-LCAT activity (i.e. LCAT activity exerted onHDL) and b-LCAT activity (i.e. LCAT activity exertedon LDL), an increased proportion (>80%) of unesterifiedcholesterol in plasma. Clinical manifestationsgenerally include corneal opacification, anaemia andrenal disease with proteinuria, which progresses toterminal renal insufficiency. In FED (OMIM No.131620), there is partial loss of a-LCAT activity withnormal or slightly elevated FC in plasma and cornealopacification without renal disease [4,5]. Intermediatephenotypes have also been described. To date, morethan 60 mutations of LCAT have been identified [4–6];they involve all regions of the coding sequence andproduce a variety of defects, including normal secretionof LCAT with total loss of catalytic activity,reduced secretion with a partial or total loss ofcatalytic activity, secretion of an unstable or rapidlycatabolized enzyme, and complete degradation of theenzyme at its site of synthesis [4]. All subjects withFED or FLD have greatly reduced plasma HDLcholesterol concentrations (usually <0.3 mmol/l) andplasma levels of apo A-I below 50 mg/dl [6,7]; however,premature coronary artery disease is absent in mostFLD cases, but sometimes present, for unclear reasons,in some patients with FED [4,6,8]. We investigated twounrelated patients with clinical features of LCATdeficiency. Two of the three LCAT mutations foundin these patients were novel
Omega 3 fatty acids for prevention and treatment of cardiovascular disease
No full textBackground: It has been suggested that omega 3 (W3, n-3 or omega-3) fats from oily fish and plants are beneficial to health.Objectives: To assess whether dietary or supplemental omega 3 fatty acids alter total mortality, cardiovascular events or cancers using both RCT and cohort studies.Search strategy: Five databases including CENTRAL, MEDLINE and EMBASE were searched to February 2002. No language restrictions were applied. Bibliographies were checked and authors contacted.Selection criteria: RCTs were included where omega 3 intake or advice was randomly allocated and unconfounded, and study duration was at least six months. Cohorts were included where a cohort was followed up for at least six months and omega 3 intake estimated.Data collection and analysis: Studies were assessed for inclusion, data extracted and quality assessed independently in duplicate. Random effects meta-analysis was performed separately for RCT and cohort data.Main results: Forty eight randomised controlled trials (36,913 participants) and 41 cohort analyses were included. Pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events in those taking additional omega 3 fats (with significant statistical heterogeneity). Sensitivity analysis, retaining only studies at low risk of bias, reduced heterogeneity and again suggested no significant effect of omega 3 fats.Restricting analysis to trials increasing fish-based omega 3 fats, or those increasing short chain omega 3s, did not suggest significant effects on mortality or cardiovascular events in either group. Subgroup analysis by dietary advice or supplementation, baseline risk of CVD or omega 3 dose suggested no clear effects of these factors on primary outcomes.Neither RCTs nor cohorts suggested increased relative risk of cancers with higher omega 3 intake but estimates were imprecise so a clinically important effect could not be excluded.Authors' conclusions: It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population. There is no evidence we should advise people to stop taking rich sources of omega 3 fats, but further high quality trials are needed to confirm suggestions of a protective effect of omega 3 fats on cardiovascular health.There is no clear evidence that omega 3 fats differ in effectiveness according to fish or plant sources, dietary or supplemental sources, dose or presence of placebo
Estudo dos polimorfismos PON1-192 e PON2-311 e atividade da enzima paroxonase em pacientes diabéticos tipo 2
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2004A paroxonase sérica humana (PON) é uma enzima localizada na HDL e está envolvida na detoxificação de organofosforados e possivelmente na prevenção da peroxidação lipídica da LDL, tendo, portanto, características antiaterogênicas. A dislipidemia é um dos principais fatores de risco para a doença arterial coronariana (DAC) que é a mais importante complicação do diabetes mellitus atingindo em torno de 50 % dos pacientes. Alguns estudos sugerem uma associação dos polimorfismos genéticos da enzima PON com o desenvolvimento de DAC e outras complicações em pacientes diabéticos tipo 2. O presente trabalho teve como objetivo avaliar o efeito dos polimorfismos PON1-192 e PON2-311 na atividade enzimática, no controle glicêmico e no perfil lipídico em 61 pacientes diabéticos tipo 2 e 82 indivíduos controle. O sangue foi coletado, após 12h de jejum, para a determinação da glicemia, insulina e hemoglobina glicada (HbA1c), colesterol total, lipoproteínas e triglicerídeos e das atividades arilesterase e paroxonase da enzima PON. O DNA foi extraído dos leucócitos do sangue periférico pelo método de extração salina. A análise dos polimorfismos foi realizada por PCR-RFLP. Não houve diferença significativa na distribuição dos genótipos e na freqüência alélica dos polimorfismos PON1-192 (QQ, RQ, RR) e PON2-311 (SS, SC, CC) entre os pacientes diabéticos e os indivíduos do grupo controle. Os valores da atividade paroxonase e arilesterase foram semelhantes para os dois grupos de participantes. O polimorfismo PON1-192 influenciou a atividade paroxonase em ambos os grupos, sendo menor nos portadores do genótipo QQ, intermediária no genótipo RQ e maior no genótipo RR (p < 0,05). A atividade paroxonase e arilesterase foi menor nos indivíduos do grupo controle portadores do genótipo PON2-311 SS. Os genótipos dos polimorfismos PON1-192 e PON2-311 não afetaram os parâmetros do controle glicêmico e do perfil lipídico nos pacientes diabéticos tipo 2, apesar dos pacientes portadores dos alelos PON1-192 R e PON2-311 C demonstrarem tendência para maiores níveis de glicose, insulina e triglicerídeos. Considerando os resultados do presente trabalho, podemos sugerir que os pacientes diabéticos tipo 2 apresentaram distribuição gênica e freqüência alélica dos polimorfismos PON1-192 e PON2-311 semelhante aos indivíduos não diabéticos. A atividade da enzima paroxonase também não foi diferente nos dois grupos de estudo. A existência de associação dos genótipos PON1-192 RR e PON2-311 CC com concentrações maiores de glicose, insulina e triglicerídeos não foi estatisticamente significante para sugerirmos a utilização desse parâmetro como indicador precoce de complicações em pacientes com diabetes mellitus tipo 2.The human serum paraoxonase (PON) is an enzyme located in the HDL and is involved in the detoxification of organophosphates and possibly in the prevention of lipid peroxidation of LDL, having, therefore, antiatherogenic characteristics. Dyslipidemia is one of the main risk factors for coronary artery disease (CAD), which is the most important complication of diabetes mellitus, affecting around 50 % of the patients. Some studies suggest an association between the genetic polymorphisms of the PON enzyme and the development of CAD and other complications in type 2 diabetic patients. This study's goal was to evaluate the effect of the PON1-192 and PON2-311 polymorphisms in the enzymatic activity, in the glycaemic control and in the lipid profile in 61 type 2 diabetic patients and 82 control individuals. The blood was collected, after a 12h fasting, to determine glucose level, insulin and glycosylated hemoglobin (HbA1c), total cholesterol, lipoproteins and triglycerides and the arilesterase and paraoxonase activities of the PON enzyme. The DNA was extracted from peripheral blood leukocytes using the saline extraction method. The analysis of the polymorphisms was made by PCR-RFLP. There was no significant difference in the genotype distribution or in the allelic frequency of the PON1-19s (QQ, RQ, RR) and PON2-311 (SS, SC, CC) polymorphisms between diabetic patients and control group individuals. The values of the paraoxonase and arylesterase activities were similar in the two groups. The PON1-192 polymorphism affected the paraoxonase activity in both groups, being smaller amongst QQ genotype individuals, intermediate for RQ genotype and greater for RR genotype individuals (p < 0,05). The smallest paraoxonase and arylesterase activities were found amongst control group individuals having PON2-311 SS genotype. The genotypes for PON1-192 and PON2-311 polymorphisms did not affect glycaemic control and lipid profile parameters in type 2 diabetic patients, although patients with the PON1-192 R and PON2-311 C alleles showed a tendency for higher levels of glucose, insulin and triglycerides. Considering the results of the present work, we can suggest that type 2 diabetic patients presented genetic distribution and allelic frequencies of the PON1-192 and PON2-311 polymorphisms similar to the non-diabetic patients. The paraoxonase enzyme activity was not different between the two studied groups. The existence of an association between the PON1-192 RR and PON2-311 CC genotypes and higher levels of glucose, insulin and triglycerides was not statistically significant to suggest the utilization of this parameter as an early indicator of complications in type 2 diabetes mellitus patients
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