Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on ...cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti-inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T-cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti-inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines.
α1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management ...of replacement therapy require the availability of precise and updated ranges for protein serum levels.
This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population.
The authors correlated mean AAT serum levels with the main SERPINA1 variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort.
The following ranges (5th-95th percentile) of AAT were found in the serum (g/litre): 1.050-1.640 for PI*MM, 0.880-1.369 for PI*MS, 0.730-1.060 for PI*SS, 0.660-0.997 for PI*MZ and 0.490-0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ).
This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based 'protective threshold' of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention.
Abstract Background After ingestion of phosphatidylcholine, l -carnitine or betaine, trimethylamine-N-oxide (TMAO) is formed by gut microbiota and liver enzymes. Elevated TMAO plasma levels were ...associated with increased cardiovascular risk and other diseases. Also betaine and choline itself were recently associated with increased cardiovascular risk. Methods A newly developed LC-HRMS method was applied to measure the plasma concentrations of TMAO, betaine and choline in a cohort of 339 patients undergoing coronary angiography for the evaluation of suspected coronary artery disease. Results Betaine concentrations in males were significantly higher than in females (42.0 vs. 35.9 μmol/L; p < 0.001). Plasma concentrations of TMAO but not of betaine or choline were higher in patients with diabetes compared to euglycemic patients (2.39 vs. 0.980 μmol/L; p = 0.001) as well as in patients with metabolic syndrome as compared to patients without metabolic syndrome (2.37 vs. 1.43 μmol/L; p = 0.002). Plasma concentrations of TMAO or choline increased significantly with decreasing renal function (Spearman's rho: −0.281; p < 0.001). However, plasma levels of TMAO or betaine were associated with neither a history of myocardial infarction nor the angiographically assessed presence of coronary heart disease, nor incident cardiovascular events during 8 years of follow-up. Plasma levels of choline were significantly lower in patients with a history of acute myocardial infarction as compared to those without such history (10.0 vs. 10.8 μmol/L; p = 0.045). Conclusions Plasma levels of TMAO are confounded by impaired kidney function and poor metabolic control but are not associated with the history, presence or incidence of symptoms or events of coronary heart disease.
Bile acids are increasingly gaining attention since they were discovered to be activators of the transcription factor farnesoid X receptor (FXR) in addition to their well-established role in dietary ...lipid emulsification. Moreover, the differential activation potency of bile acids on FXR, which is due to structural variation of the ligands, generates the need for new analytical tools that are sensitive and specific enough to quantify the individual species of this complex class of compounds. Because bile acids undergo enterohepatic circulation, the additional assessment of a bile acid precursor as a marker for bile acid biosynthesis is used to differentiate between newly synthesised bile acids and bile acids reabsorbed from the intestine. This paper describes two new methods using liquid chromatography–tandem mass spectrometry (LC–MS/MS) for the quantification of the major unconjugated bile acids in human serum (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid and ursodeoxycholic acid) with their glycine- and taurine-conjugates as well as their precursor 7α-hydroxy-4-cholesten-3-one (C4). Intra- and inter-day variation was less than 12% and accuracy was between 84% and 102% for all analytes. Extraction recovery was between 78% and 100% for the bile acids whereas it was 62% for C4 and limit of quantification values ranged from 2
nmol/l to 50
nmol/l for all compounds. These two methods have the practical advantage of requiring low sample volume (100
μl serum for each method) and identical eluents, stationary phase as well as ionisation technique, so that they can be used in a combined way. Moreover, they provide information on the composition of the bile acid pool on one hand and on the relative amount of newly synthesised bile acids on the other, which taken together, gives new insights in the investigation of bile acid metabolism.
SPT (serine palmitoyltransferase) catalyses the rate-limiting step for the de novo synthesis of sphingolipids. Mammalian SPT is believed to be a heterodimer composed of two subunits, SPTLC1 and ...SPTLC2. We reported previously the identification of a new third SPT subunit, SPTLC3. In the present study, we have investigated the structure of the SPT complex in more detail. Pull-down assays with antibodies against SPTLC3 concomitantly co-precipitated SPTLC1 and SPTLC2 in human placenta extracts and SPTLC3 overexpressing human embryonic kidney-293 cells. By size exclusion chromatography, we determined the molecular mass of the functional SPT complex to be approx. 480 kDa. By Blue-native-PAGE experiments we demonstrated that all three SPT subunits (SPTLC1-3) are co-localized within a single SPT complex. On the basis of these results we conclude that the functional SPT is not a dimer, but a higher organized complex, composed of three distinct subunits (SPTLC1, SPTLC2 and SPTLC3) with a molecular mass of 480 kDa. The stoichiometry of SPTLC2 and SPTLC3 in this complex seems not to be fixed and is probably changed dynamically in dependence of the tissue specific SPTLC2 and SPTLC3 expression levels. Based on our own and earlier published data we propose a model of an octameric SPT structure. The observed dynamic composition of the SPT complex could provide a cellular mechanism to adjust SPT activity to tissue specific requirements in sphingolipid synthesis.
The inverse correlation between serum levels of high density lipoprotein (HDL) cholesterol and the risk of coronary heart disease, the protection of susceptible animals from atherosclerosis by ...transgenic manipulation of HDL metabolism, and several potentially anti-atherogenic in vitro-properties have made HDL metabolism an interesting target for pharmacological intervention in atheroslcerosis. We have previously reviewed the concept of reverse cholesterol transport, which describes both the metabolism and the classic anti-atherogenic function of HDL (Arterioscler. Thromb. Vasc. Biol. 20 2001 13). We here summarize the current understanding of additional biological, potentially anti-atherogenic properties of HDL. HDL inhibits the chemotaxis of monocytes, the adhesion of leukocytes to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, complement activation, platelet activation and factor X activation but also stimulates the proliferation of endothelial cells and smooth muscle cells, the synthesis of prostacyclin and natriuretic peptide C in endothelial cells, and the activation of proteins C and S. These anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities are exerted by different components of HDL, namley apolipoproteins, enzymes, and even specific phospholipids. This complexity further emphasizes that changes in the functionality of HDL rather than changes of plasma HDL-cholesterol levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism.
The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein ...quantification for cardiovascular risk management.
We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (
) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (
) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (
) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol.
Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It ...has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D.
The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings.
Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.
Low HDL cholesterol and hypertriglyceridemia as well as lowering of LDL cholesterol with statins increase the risk of T2DM. We discuss the recent findings on the effects of lipoproteins and ...cholesterol on the function and survival of pancreatic β-cells as well as on obesity and insulin sensitivity of muscle and liver.
LDL inhibits glucose-stimulated insulin secretion and proliferation of β-cells by LDL-receptor dependent and independent mechanisms, respectively. ApoA-I and HDL stimulate insulin secretion by interaction with ABCA1, ABCG1 or SR-BI and also inhibit apoptosis of β-cells. Mice with targeted knockouts of ABCA1 or ABCG1 in β-cells show reduced insulin secretion and glucose tolerance. ABCG1 contributes to the enrichment of insulin secretory granules with cholesterol, which is needed for their formation and trafficking to the plasma membrane whereas ABCA1-mediated cholesterol efflux from the plasma membrane appears to be important for their subsequent exocytosis. In mice, overexpression of apoA-I decreases body fat accumulation and increases insulin sensitivity of muscle and liver by inducing the phosphorylation of AMP kinase.
LDL, HDL and cholesterol regulate the function and survival of β-cells. HDL also exerts antiobesity and insulin-sensitizing effects. Thus dyslipidemias may not only be consequences but also contributors to the pathogenesis and hence targets for prevention of T2DM.
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