Very low HDL levels: clinical assessment and management

ABSTRACT In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree of association between the HDL system and atherosclerotic risk, but as they were not designed to modify lipoprotein functionality, there is insufficient data to establish a causal relationship. We currently have randomized clinical trials of therapies that increase HDL-C concentration by various mechanisms, and this HDL-C elevation has not independently demonstrated a reduction in the risk of cardiovascular events. Therefore, this evidence shows that (a) measuring HDL-C as a way of estimating HDL-related atheroprotective system function is insufficient and (b) we still do not know how to increase cardiovascular protection with therapies aimed at modifying HDL metabolism. This leads us to a greater effort to understand the mechanisms of molecular action and cellular interaction of HDL, completely abandoning the traditional view focused on the plasma concentration of HDL-C. In this review, we will detail this new understanding and the new horizon for using the HDL system to mitigate residual atherosclerotic risk.

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class ofmedication that mainly lowers theblood triglyceride levels. Theyreduce the LDL andincrease the levels of HDL C, in the blood.Clofibrate,the first member to bediscovered in 1962, and introduced in USA in 1967, is withdrawnin 2002, due to unexplained hepatomegaly,hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular diseaseand diabeticretinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial andangiography trials, like LOCAT(LopidCoronary Angiography Trial) and BECLAIT(Bezafibrate Coronary Atherosclerosis Intervention Trial)demonstrated thebeneficial effects of gemfibrozil and fenofibrate.Their mechanism of action remained obscure for three decades,ie till 1990s, when theirmode of actionwas found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involvingthevariousenzymes like LCAT (Lecithin-cholesterol acyl transferase)andCYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochromeP450 7A1 (CYP7A1)) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP,OATP (Na+-dependent taurocholate transporter/ organic anion transporters) . These are the.) andnuclear factors like LXR, PPAR alfa etc. (liver orphan receptorα , and peroxisome proliferative nuclear factor) , in relation to the mechanismsof action of fibrates are discussed . Areas of current interests in literature are briefed.

Efeito da administração In Bolus da heparina sódica no remodelamento de partículas lepoprotéicas associadas ao transporte reverso do colesterol / In bolus administration the effect of heparin sodium in remodeling lepoprotéicas particles associated with reverse cholesterol transport

Introdução: as doenças cardiovasculares acometem milhares de pessoas no mundo. Destas, a doença arterosclerótica está entre as de maior morbimortalidade. Para a avaliação da necessidade de intervenções hemodinâmicas e/ou revascularização miocárdica, há a necessidade da realização do cateterismo (CATE), procedimento de imagem indicado para evidenciar pontos de obstrução e determinar a melhor estratégia cirúrgica. Para a realização do CATE utiliza-se heparina sódica (5000 UI) in bolus. Atualmente, sabe-se que a heparina interfere no remodelamento de partículas lipoproteicas por liberação da lipoproteína lipase (LPL) e da lipase hepática (LH), essa ação pode alterar o transporte reverso do colesterol (TRC), em função de modificações no metabolismo das lipoproteínas. Métodos: foram selecionados por conveniência 20 pacientes, 10 do sexo masculino e 10 do sexo feminino, ambos os sexos, entre 45 e 73 anos, admitidos no Hospital Ana Neri, submetidos à cineangiocoronariografia (CATE)...

Introduction: cardiovascular diseases affect thousands of people worldwide. Of these, the atherosclerotic disease is one of the most morbidity and mortality. To evaluate the need for hemodynamic interventions and / or CABG, the catheterization (CATE) is performed, an imaging procedure to evidence obstruction and to determine the best surgical strategy. To perform CATE, is necessary to use in bolus sodium heparin (5000 IU). Currently, it is known that heparin interferes with the remodeling of the lipoprotein particles by releasing lipoprotein lipase (LPL) and hepatic lipase (HL), this action may alter the reverse cholesterol transport (TRC), by changes in lipoprotein metabolism. Methods: were selected by convenience 20 patients, 10 male and 10 female, both gender, between 45 and 73 years old, admitted to the Hospital Ana Neri, who underwent coronary angiography (CATE)...

Role of Magnesium Supplement on Hyperlipidemia and L-CAT Level in Patient on Atorvastatin Therapy.

Aim: This study aimed to evaluate the effect of magnesium supplement to atorvastatin on hyperlipidemic patients and to elucidate the possible ability of oral magnesium supplement to counteract or delay statins induced myalgia. Study Design: Forty hyperlipidemic male and female patients were randomly divided into two groups: group one consisted of twenty patients, who received atorvastatin 10 mg once daily for 6 weeks then 20 mg once daily for another 6 weeks; group two consisted of twenty patients, who received the same dose of atorvastatin plus once daily oral low dose magnesium sulfate trihydrate 419.5 mg equivalent to 50 mg of magnesium. Place and Duration of Study: The Laboratory of Pharmaceutical Research Center of Faculty of Pharmacy, Tanta University, Egypt, between July to December 2013. Methodology: Two samples of venous blood (2 ml + 8 ml =10 ml total), were collected from all individuals, and were drawn from the antecubital vein before, 1.5 and 3 months after treatment. Sera and plasma were separated immediately for biochemical analyses of lecithin cholesterol acyltransferase (L-CAT) (ELISA), creatine kinase (CK), serum Ca+, Mg++, Na+, K+, lipid profile and aspartate transaminase (AST) (colorimetrically), and serum creatinine (S.Cr) spectrophotometrically. Results: The statistical analysis revealed that, 3 months after treatment, both groups showed significant amelioration in lipid profiles and significant elevation in L-CAT level regarding to baseline data obtained before initiation of treatment. In addition, the patients received atorvastatin plus magnesium supplement showed significantly higher levels of serum magnesium, plasma L-CAT and HDL-cholesterol concentrations and significantly lower total cholesterol, LDL-cholesterol and triglycerides concentrations with non significant lower CK level as compared to the patients group received atorvastatin solely. Conclusion: Mg++ supplement to atorvastatin improve all lipid profile and provide better control on dyslipidemia than atorvastatin alone. However, Mg++ supplement to atorvastatin doesn’t prevent elevation in CK; it may delay and provide some protection against statin induced myopathy that in turn may increase patient compliance.

Activity of Lecithin Cholesterol Acyl Transferase and Apolipoprotein A-I in Newly Detected Type 2 Diabetes mellitus.

Aims: 1. To study the levels of Apolipoprotein A-I and activity of Lecithin cholesterol acyl transferase (LCAT) in newly detected type 2 Diabetes Mellitus. Study Design: Cross sectional study. Place and Duration of Study: Department of Biochemistry and Department of Medicine, Belgaum Institute of Medical Sciences (BIMS), Belgaum, Karnataka, India, between November 2011 and June 2013. Methods: Study included 100 patients (50 men, 50 women, age range 30-60 years) with newly detected type 2 Diabetes Mellitus and 100 age and sex matched healthy participants. LCAT activity was assessed by measuring the difference between esterified and free cholesterol. Determination of free and esterified cholesterol was done by using digitonin precipitation method. Apolipoprotein A-I was measured by immunoturbidemetric method using semi auto analyzer. HDL cholesterol level was measured by CHOD-POD method. Results: The mean±SD value of various parameters in newly detected type 2 Diabetes Mellitus was HDL cholesterol(33.37±4.44mg/dl), Apolipoprotein A-I(133.10±24.22mg/dl), and LCAT activity(59±9.86 IU/L), versus HDL cholesterol(48.76±16.84mg/dl), Apolipoprotein A-I(188.72±19.49mg/dl) and LCAT activity (91.74±6.50IU/L) in controls. LCAT activity, Apolipoprotein A-I and HDL levels were significantly (p < 0.01) decreased in patients with newly detected type 2 Diabetes Mellitus when compared with healthy participants. Conclusion: The reduced LCAT activity, Apolipoprotein-A-I and HDL cholesterol may be associated with a reduction in Reverse cholesterol transport(RCT) and contribute to the development of atherosclerosis in newly detected type 2 Diabetes Mellitus.

A Case of Familial Lecithin-cholesterol Acyltransferase (LCAT) Deficiency

PURPOSE: To report a case of a familial lecithin cholesterol acyltransferase (LCAT) deficiency patient with bilateral corneal opacities. CASE SUMMARY: A 26-year-old man with bilateral corneal opacities visited our hospital. We took slit lamp examination, corneal thickness measurement, corneal endothelial cell counts and fundus examination. Blood and urine tests were included. Kidney biopsy was done. The tissues were observed by a light microscopy and an electron microscopy. Hemolytic anemia, proteinuria, hematuria, hypertriglyceridemia, decreased HDL cholesterol level, and lecithin cholesterol acyltransferase (LCAT) deficiency were found. At kidney biopsy, electron-lucent vacuoles and lamellar inclusion body were found. CONCLUSIONS: Bilateral corneal opacities can be an imporant clinical sign of systemic disease which is caused by abnormal lipid metabolism like the familial lecithin cholesterol acyltransferase (LCAT) deficiency.

Efeito de tratamento cirúrgico sobre a atividade da enzima hepática lecitina: colesterol aciltransferase (LCAT) na esquistossomose mansônica

Schistosomiasis mansoni is a tropical disease and remains as an important public healthy problem in Northeast - Brazil, where it is highly endemic. This disease has the liver as the major focus of its histological lesions, physiopathological alterations and clinical manifestations. Previous studies have shown alteration on lipid metabolism in the hepatosplenic form of Schistosomiasis. One of the main alterations is the reduction on lecithin: cholesterol acyltransferase (LCAT) activity, an hepatic enzyme that catalyze the esterification of cholesterol in plasma In this work, we evaluate the LCAT activity in plasma from patients with hepatosplenic Schistosomiasis mansoni who were subjected to a new surgical treatment, which consists of splenectomy followed by auto-transplantation of spleen tissue. LCAT activity was detected by using a radioactive substrate. Both [14C]free and esterified cholesterol produced by the LCAT reaction were separated by thin layer chromatography, and the sample radioactivity was counted in a liquid scintilation analyzer. LCAT activity from plasma of patients subjected to splenectomy and spleen tissue implantation were reduced by 32 %, in comparison to the control group. However, in Schistosoma mansoni patients who were only clinically treated the reduction on LCAT activity was twice (64%) as much as that found in plasma of patients subjected to splenectomy and spleen tissue implantation. These results suggest a significant improvement on LCAT activity after the surgical treatment of patients with the hepatosplenic form of Schistosomiasis mansoni.

A esquistossomose mansônica é uma doença tropical que constitui um importante problema de saúde pública, na Região Nordeste do Brasil, onde é encontrada em alta endemicidade. Essa parasitose tem o fígado como principal alvo de suas lesões histológicas, alterações fisiopatológicas e manifestações clínicas. Estudos anteriores reportam alterações no metabolismo lipídico associadas à forma hepatoesplênica da esquistosomose.Uma das principais alterações consiste na redução da atividade da enzima hepática LCAT, responsável pela esterificação do colesterol no plasma. Neste trabalho, avaliamos a atividade da LCAT no plasma de pacientes portadores da esquistossomose mansônica hepatoesplênica, os quais foram submetidos a esplenectomia e reimplante de parte de tecido do baço. A atividade enzimática da LCAT foi determinada com substrato radioativo. O [14C]colesterol livre e esterificado, formados por ação da LCAT, foram separados por cromatografia em camada delgada e a radioatividade das amostras foi contada em analisador de cintilação líquida. A atividade da LCAT nos pacientes submetidos a esplenectomia e reimplante de tecido do baço apresentou redução de 32 %, em relação ao grupo controle. Contudo, nos portadores da doença que não foram submetidos ao procedimento cirúrgico a redução na atividade da LCAT foi o dobro (64%) da observada em pacientes esplenectomizados e com reimplante de parte do tecido do baço. Esses resultados sugerem haver uma melhora significativa no efeito da forma grave da esquistossomose mansônica sobre a atividade da LCAT.

Serum lipid levels in female handball players / 体力科学

Serum lipid levels in female handball players were studied. A group of well trained female handball players, in comparison with a group of less active females, had a significantly lower level of triglyceride, higher levels of HDL-cholesterol and HDL<SUB>2</SUB>-Cholesterol subfractions, and higher apolipoprotein A-I and LCAT activities. The ratio of apolipoprotein B/apolipoprotein A-I, as an atherogenic index, was also significantly lower in the handball players. These results suggest that prolonged regular exercise such as handball training may produce favorable changes in serum lipids, thus helping to prevent and reduce the incidence of atherosclerosis.

Hypolipidemic principle of the inflorescence stalk of plantain (Musa sapientum).

A pectin present in the juice of the inflorescence stalk of plantain (Musa sapientum) has been isolated. The material contained 32·4% hexoses and 52·5% uronic acid. On administration to rats fed both cholesterol free and cholesterol diet, this material showed significant lowering of cholesterol and triglycerides in the serum, liver and aorta. There was decreased cholesterogenesis in the liver as was evident from decreased activity of hydroxymethylglutaryl coenzyme A reductase and decreased incorporation of labelled acetate into hepatic cholesterol. Hepatic bile acids showed significant increase and there was increased fecal excretion of neutral sterols and bile acids. Release of lipoproteins into the circulation was lower. The material also caused increase in the activity of lipoprotein lipase in the heart and adipose tissue and also of plasma lecithin: cholesterol acyl transferase.

Mechanism of hypercholesterolemia produced by biotin deficiency.

The effect of biotin deficiency on the metabolism of cholesterol was studied in rats fed cholesterol-free and cholesterol-containing diet. Biotin deficiency induced by feeding raw egg-white resulted in higher cholesterol in the serum and aorta, and higher high density lipoprotein cholesterol and low density lipoprotein + very low density lipoprotein cholesterol. In the liver, cholesterol increased only in the cholesterol diet group but not in the cholesterol-free diet group. Levels of triglycerides were lower in the biotindeficient, cholesterol-free diet group, but triglycerides were elevated in the cholesterol diet group. Concentration of bile acids in the liver and activity of lipoprotein lipase in the heart and adipose tissue were significantly decreased in the biotin-deficient rats. Release of lipoproteins into the circulation, incorporation of [1,2-14C] acetate into cholesterol, and activity of plasma lecithin: cholesterol acyl transferase were higher.

Effect of physical training on the metabolism of serum and arterial cholesterol / 体力科学

The effect of a treadmill running program on the metabolism of cholesterol in serum and in arterial wall was studied in male Wistar rats, aged 7 weeks and weighing about 200 g- Rats were exercised on 6 days a week for 8 week, running 1, 000 m a day at 15 m/min. The trained rats gave the follwing evidence, as compared with the sedentary control animals:<BR>1. Remarkably lower body weight<BR>2. Significantly lower level of serum cholesterol-total, free, and LDL cholesterol<BR>3. Elevated in vivo incorporation of <SUP>14</SUP>C-mevalonate into serum cholesterol<BR>4. Enhancement of lecithin-cholesterol acyltransferase activity in serum<BR>5. Decrease in the amount of cholesterol in arterial wall cells<BR>6. Increase in in vivo incorporation of <SUP>14</SUP>C-mevalonate into arterial cholesterol.<BR>The results indicate that the excersice promotes the turnover of cholesterol in serum and arterial wall, repressing the accumulation of choleterol ester in arterial wall cells, and a prophylactic effect of the physical training for arteriosclerotic diseases has been suggested.