Changes In Lipoprotein Metabolism Research Articles

Serum il-18 and rs187238 single nucleotide polymorphism are associated with high-density lipoprotein changes in covid-19 outpatients

AimCOVID-19 is an inflammatory disease and its prognosis is associated with cardiovascular risk, which can be associated with changes in lipoprotein metabolism. The single nucleotide polymorphism (SNP) rs187238 of Interleukin (IL)-18 is extensively reported in association with worsening inflammatory and cardiovascular disease (CVD). This study evaluated the association of IL-18 levels and its SNP rs187238 with lipoprotein profile changes in COVID-19 outpatients. MethodsObservational, analytical, cross-sectional study that evaluated 250 patients with respiratory syndrome, 36% (n = 90) with COVID-19. Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apolipoproteins A-I and B (Apo A-I and Apo B) and IL-18 levels were determined. Polymorphism genotyping was done by real-time polymerase chain reaction (qPCR). The significance level was p < 0.05. ResultsPatients with COVID-19 showed a reduction in TC and HDL-c, without difference in IL-18. HDL-c and LDL-c had a high frequency outside the reference values. There was a negative correlation of IL-18 with HDL-c and a positive correlation with Apo B/Apo A-I ratio. The frequencies of the C (wild) and G (polymorphic) alleles between patients with and without COVID-19 followed the Hardy-Weinberg equilibrium. However, COVID-19 was associated with reduced HDL-c and Apo A-I values in patients with the CC genotype. ConclusionIL-18 levels and its SNP rs187238 were associated with decreased HDL-c and Apo A-I in COVID-19 outpatients.

Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer's Disease Patients.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and has been associated with changes in lipoprotein metabolism. We performed quantitative lipoprotein analysis in a local cohort of cognitively impaired elderly and control subjects using standardized nuclear magnetic resonance (NMR) spectroscopy. A commercially available quantitative NMR-based assay covering 112 lipoprotein main and subtype variables was used to investigate blood serum samples from a moderate cohort size of 161 persons (71 female, 90 male), including measures of quality control. Additionally, clinical metadata and cerebrospinal fluid AD biomarkers were collected and used for analysis. High-density lipoprotein (HDL) HDL-4 subfraction levels were mostly high in female individuals with mild cognitive impairment (MCI), followed by AD. Low-density lipoprotein (LDL) LDL-2 cholesterol was slightly elevated in male AD patients. HDL-2 apolipoprotein Apo-A1, HDL-2 phospholipids, and HDL-3 triglycerides were highly abundant in AD and MCI women compared to men. When considering clinical biomarkers (Aβ, tau), very low-density lipoprotein (VLDL) VLDL-1 and intermediate-density lipoprotein (IDL) triglycerides were substantially higher in AD compared to MCI. In addition, triglyceride levels correlated positively with dementia. Different lipoprotein serum patterns were identified for AD, MCI, and control subjects. Interestingly, HDL-4 and LDL-2 cholesterol parameters revealed strong gender-specific changes in the context of AD-driven dementia. As gender-based comparisons were based on smaller sub-groups with a low n-number, several statistical findings did not meet the significance threshold for multiple comparisons testing. Still, our finding suggests that serum HDL-4 parameters and various triglycerides correlate positively with AD pathology which could be a read-out of extended lipids traveling through the blood-brain barrier, supporting amyloid plaque formation processes. Thereof, we see herein a proof of concept that this quantitative NMR-based lipoprotein assay can generate important and highly interesting data for refined AD diagnosis and patient stratification, especially when larger cohorts are available.

A case of tamoxifen-induced hypertriglyceridemia monitoring the changes in lipoprotein fractions over time

BackgroundTamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it.Case presentation47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically.ConclusionsFrom these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.

Long term Depot Medroxy Progesterone Asetate (DMPA) Injectable Increase Changes in Lipid Profiles of DMPA Injection Contraceptive Acceptors

DMPA injectable contraceptives can cause changes in lipoprotein metabolism. Long term use of DMPA increases triglyceride levels, total cholesterol and LDL and decreases HDL levels. So, it can be concluded that DMPA can cause changes in lipid metabolism which can increase the risk of cardiovascular disease. Changes in fat metabolism occur due to the influence of the hormonal progesterone, which causes disruption of the balance of the lipid profile in the body. The purpose of this study was to determine the effect of using Depo Medroxy Progeserone Acetate injection on the lipid profile of three months injection family planning acceptors based on the duration of use.This research is an analytic observational study with a cross sectional approach, the population in this study were all DMPA family planning acceptors in the work area of ​​the Banjar Sengon Community Health Center, the sampling technique used was total sampling with a sample size of 30. Examination of the lipid profile was carried out by taking blood samples and then measuring them. lipid profile using the enzymatic colorimetric method (cholesterol oxidase method / CHOD PAP). The measurement results obtained were then analyzed using the Independent T test. The results of the T test analysis showed that the P value for cholesterol levels was 0.016 (P &lt;0.05); The p value for triglyceride levels was 0.004 (P &lt;0.05); The p value for HDL levels was 0.046 (P &lt;0.05); The p value for LDL levels was 0.004 (P &lt;0.05).From these data it can be concluded that there is a significant difference in the average levels of cholesterol, triglycerides, HDL, LDL between respondents with a duration of use &lt;3 years and&gt; 3 years. Respondents are expected to carry out routine lipid profile checks to detect early detection of possible abnormalities in lipid profiles that can lead to the risk of heart defects and stroke.

The Description of Lipid Profile on Injectable DMPA Contraception Acceptors in Public Health Center Banjarsengon, Jember District

Injectable DMPA contraception can cause changes in lipoprotein metabolism. Changes in fat metabolism occur because of the hormonal influence of progesterone, causing disruption of the balance of lipid profiles in the body. The change in serum lipid profile (trgliseride, total cholesterol, HDL and LDL) in long-term use of DMPA is a risk factor for atherosclerosis and cardiovascular disease. The purpose of this study was to look at the description of the lipid profile at 3 months injection acceptors. The design of the study was descriptive. The population in this study was 76, the number of samples that met the inclusion and exclusion criteria in this study was 30. Examination of the lipid profile was carried out with an enzymatic colorimetric (cholesterol oxidase method / CHOD PAP). The results of lipid profile examination showed that 13.33% had high cholesterol levels, 3.33% had high triglyceride levels, 13.33% had high HDL levels, 20% had high LDL levels and 3.33% have very high LDL levels. The conclusion of this study was long term use of DMPA injection contraception could cause changes in the lipid profile, so it is recommended for acceptors who want to use contraception in the long term to use MKJP as an option so as not to affect the fat profile in the body.

Pregnancy is accompanied by larger high density lipoprotein particles and compositionally distinct subspecies

Pregnancy is accompanied by significant physiological changes, which can impact the health and development of the fetus and mother. Pregnancy-induced changes in plasma lipoproteins are well documented, with modest to no impact observed on the generic measure of high density lipoprotein (HDL) cholesterol. However, the impact of pregnancy on the concentration and composition of HDL subspecies has not been examined in depth. In this prospective study, we collected plasma from 24 nonpregnant and 19 pregnant women in their second trimester. Using nuclear magnetic resonance (NMR), we quantified 11 different lipoprotein subspecies from plasma by size, including three in the HDL class. We observed an increase in the number of larger HDL particles in pregnant women, which were confirmed by tracking phospholipids across lipoproteins using high-resolution gel-filtration chromatography. Using liquid chromatography-mass spectrometry (LC-MS), we identified 87 lipid-associated proteins across size-speciated fractions. We report drastic shifts in multiple protein clusters across different HDL size fractions in pregnant females compared with nonpregnant controls that have major implications on HDL function. These findings significantly elevate our understanding of how changes in lipoprotein metabolism during pregnancy could impact the health of both the fetus and the mother.

Dose Effects of Ammonium Perfluorooctanoate on Lipoprotein Metabolism in APOE*3-Leiden.CETP Mice.

Epidemiological studies have reported positive associations between serum perfluorooctanoic acid (PFOA) and total and non-high-density lipoprotein cholesterol (non-HDL-C) although the magnitude of effect of PFOA on cholesterol lacks consistency. The objectives of this study were to evaluate the effect of PFOA on plasma cholesterol and triglyceride metabolism at various plasma PFOA concentrations relevant to humans, and to elucidate the mechanisms using APOE*3-Leiden.CETP mice, a model with a human-like lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFOA (10, 300, 30 000 ng/g/d) for 4–6 weeks. PFOA exposure did not alter plasma lipids in the 10 and 300 ng/g/d dietary PFOA dose groups. At 30 000 ng/g/d, PFOA decreased plasma triglycerides (TG), total cholesterol (TC), and non-HDL-C, whereas HDL-C was increased. The plasma lipid alterations could be explained by decreased very low-density lipoprotein (VLDL) production and increased VLDL clearance by the liver through increased lipoprotein lipase activity. The concomitant increase in HDL-C was mediated by decreased cholesteryl ester transfer activity and changes in gene expression of proteins involved in HDL metabolism. Hepatic gene expression and pathway analysis confirmed the changes in lipoprotein metabolism that were mediated for a major part through activation of the peroxisome proliferator-activated receptor (PPAR)α. Our data confirmed the findings from a phase 1 clinical trial in humans that demonstrated high serum or plasma PFOA levels resulted in lower cholesterol levels. The study findings do not show an increase in cholesterol at environmental or occupational levels of PFOA exposure, thereby indicating these findings are associative rather than causal.

Abstract 167: Mechanism of Increased Low Density Lipoprotein Cholesterol and Decreased Triglycerides with Sodium-glucose Co-transporter 2 Inhibition

Objective: Although Sodium glucose cotransporter 2 (SGLT2) inhibition in humans sometimes leads to increased levels of low density lipoprotein (LDL) cholesterol, this therapy is associated with marked reduction in cardiovascular disease. In this study, we aimed to determine how SGLT2 inhibition alters circulating lipoproteins. Approach and Results: We used a mouse model in which plasma lipoprotein profiles were humanized by expression of human cholesteryl ester transfer protein and human apolipoprotein B100 to determine how SGLT2 inhibition alters lipoprotein profiles. The mice were fed a high fat diet and then were made partially insulin deficient using streptozotocin. SGLT2 was inhibited using a specific anti-sense oligonucleotide or canagliflozin, a clinically available oral SGLT2 inhibitor. Inhibition of SGLT2 increased circulating levels of LDL cholesterol and reduced plasma triglyceride levels. SGLT2 inhibition was associated with increased lipoprotein lipase activity in the post heparin plasma and decreased postprandial lipemia. The changes in lipoprotein metabolism were more significant in mice treated with SGLT2 ASO compared to canagliflozin. Conclusions: Our studies in mice recapitulate many of the changes in circulating lipids found with SGLT2 inhibition therapy in humans and suggest that the increased LDL cholesterol found with this therapy is due to greater lipolysis of triglyceride-rich lipoproteins. This change in lipoprotein physiology is likely, in part, to explain the reduced cardiovascular disease found with SGLT2 inhibition.

Ernährungsempfehlungen beim metabolisch-vaskulären Syndrom

Cardiovascular disease is the number one cause of death globally. Poor diet constitutes a key factor in the initiation and progression of cardiovascular disease and has become the leading risk factor for disability and death worldwide. Therefore, addressing suboptimal nutrition is of key prognostic relevance in primary and secondary prevention of metabolic vascular syndrome. Metabolic vascular syndrome is a multidimensional network of acquired cardiometabolic risk factors closely related to insulin resistance (IR) and concomitant hyperinsulinemia. IR, being the underlying cause of metabolic vascular syndrome and certain types of cancer, should attract the attention of every clinician. As changes in lipoprotein metabolism are one of the earliest indicators of metabolic dysfunction, a relevant biomarker for identifying individuals with IR is the TAG/HDL-C ratio. IR – and concomitant metabolic vascular risk – can be effectively treated by lifestyle intervention. If IR is present, dietary carbohydrate restriction has consistently been shown to be superior to dietary fat restriction in reversing metabolic dysfunction. The beneficial effects of carbohydrate restricted diets on metabolic vascular risk are independent of BMI – diet quality therefore confers patient benefit beyond weight reduction. The effect of single nutrients on isolated lipid surrogate markers such as LDL-C does not capture their global effect on metabolic vascular risk. Targeting IR with a low glycemic load, real food diet will reduce overall energy density and will improve all risk factors of metabolic vascular syndrome. In particular, replacing refined carbohydrates with healthy fats in the context of a Mediterranean style-, low carbohydrate and calorie-unrestricted dietary pattern has been shown to significantly reduce burden of metabolic vascular disease.

Ernährungsempfehlungen beim metabolisch-vaskulären Syndrom

Cardiovascular disease is the number one cause of death globally. Poor diet constitutes a key factor in the initiation and progression of cardiovascular disease and has become the leading risk factor for disability and death worldwide. Therefore, addressing suboptimal nutrition is of key prognostic relevance in primary and secondary prevention of metabolic vascular syndrome.Metabolic vascular syndrome is a multidimensional network of acquired cardiometabolic risk factors closely related to insulin resistance (IR) and concomitant hyperinsulinemia. IR, being the underlying cause of metabolic vascular syndrome and certain types of cancer, should attract the attention of every clinician. As changes in lipoprotein metabolism are one of the earliest indicators of metabolic dysfunction, a relevant biomarker for identifying individuals with IR is the TAG/HDL-C ratio.IR - and concomitant metabolic vascular risk - can be effectively treated by lifestyle intervention. If IR is present, dietary carbohydrate restriction has consistently been shown to be superior to dietary fat restriction in reversing metabolic dysfunction. The beneficial effects of carbohydrate restricted diets on metabolic vascular risk are independent of BMI - diet quality therefore confers patient benefit beyond weight reduction.The effect of single nutrients on isolated lipid surrogate markers such as LDL-C does not capture their global effect on metabolic vascular risk.Targeting IR with a low glycemic load, real food diet will reduce overall energy density and will improve all risk factors of metabolic vascular syndrome. In particular, replacing refined carbohydrates with healthy fats in the context of a Mediterranean style-, low carbohydrate and calorie-unrestricted dietary pattern has been shown to significantly reduce burden of metabolic vascular disease.

Breaking up sedentary time, physical activity and lipoprotein metabolism.

Some authors report delayed responses of lipid metabolism after prolonged and interrupted sitting. To date no experimental studies have shown acute physical activity (PA) related changes of lipoprotein metabolism during sedentary behavior (SB). The purpose of this study was to examine immediate effects of a single PA-bout vs. regular PA-breaks on lipoprotein metabolism during postprandial SB. Eighteen female subjects (25.6years±2.6; 21.5kg/m2±2.0) participated in a balanced crossover experiment with three trials: (1) 30min PA prior to 4h sitting (PRE), (2) 5×6min PA within 4h sitting (BREAK) (3) 4h sitting (CTRL). PA was ergometer cycling at 70%VO2max. Participants consumed one standardized breakfast in each trial. Total cholesterol (tChol), high density lipoprotein (HDL), low density lipoprotein (LDL) and triacylglycerol (TAG) readings were taken in fasted state at the beginning (before), and immediately after each trial. Multiple 2×3-ANOVAs (trial-arm*time) and post hoc t-tests were used. ANOVAs revealed trial*time-effects for tChol (p=0.043) and HDL (p=0.007) and a tendency for LDL (p=0.078). Before-to-after differences (Δ) of tChol during BREAK-trial (-0.89±5.49mg/dl) significantly differed to Δ during PRE-trial (+3.56±5.32mg/dl) (p=0.005) but not to ΔCTRL (+2.16±8.72). ΔHDL during BREAK-trial (-2.11±3.31mg/dl) significantly differed to ΔPRE (+0.83±4.26mg/dl) (p=0.007) and ΔCTRL (+0.06±4.15mg/dl) (p=0.028). Analysis of TAG revealed a time effect (p=0.007) and significant differences between TAG before and after trial within BREAK (79.22±38.69mg/dl to 94.78±44.86mg/dl) and CTRL (80.94±32.94mg/dl to 97.72±41.19mg/dl) but not in PRE (78.83±33.13mg/dl to 89.06±33.83mg/dl). Breaking sedentary behavior with vigorous intensity PA seem to decelerate postprandial lipoprotein metabolism during sitting. In contrast, prior PA, might be a stimulus for lipid metabolization.

Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

Aim: Increased susceptibility for atherosclerotic cardiovascular disease attributable to low-normal thyroidfunction is likely to be in part be due to effects on plasma lipoproteins. Associations of changes in lipoprotein metabolism with thyroid function could be enhanced in the context of chronic hyperglycemia. We determined relationships of plasma lipids and lipoprotein subfractions with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM).

Low–normal thyroid function and the pathogenesis of common cardio‐metabolic disorders

Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). This narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and PubMed up to November 2014. Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far. Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far.

131-POS

Objectives Preeclampsia is a life-threatening disorder of late gestation of unknown origin. Soluble fms-like tyrosine kinase 1 (sFlt-1) is discussed as marker, but also as pathogenic factor for preeclampsia. Thus, removal of sFlt-1 by dextran-sulfate apheresis is suggested to be causative for clinical improvements in preeclampsia. However, as shown by Wang et al. (2006) heparin-mediated extracorporeal low-density lipoprotein precipitation (HELP) apheresis not addressing sFlt showed similar clinical benefits, whereas both techniques lower low density lipoprotein (LDL) cholesterol by at least 60%. Hence, LDL may play a pivotal role in the pathogenesis of preeclampsia. Methods Changes of lipoprotein metabolism during normal pregnancy (NP) and the association to preeclampsia were shown previously (Winkler et al., 2000, 2003). From this clinical data-set we now present compositional data of LDL during NP and in preeclampsia. Results During pregnancy the ratio of triglycerides/cholesterol (TG/CH) in LDL raises steadily, peaks around delivery and drops to almost non-pregnant values within 4 weeks postpartum (Figure). At the 33rd gestational week (g.w.) the TG/CH-ratio of preeclampsia was significantly higher compared to NP, both at the 34th g.w. and at birth. At the 33rd g.w. a TG/CH-threshold of ⩾ 0.21 [mmol/mmol] discriminates PE from NP (34th g.w.) with a sensitivity and specificity of 80% and 91%, respectively. Conclusions The LDL TG/CH-ratio may have some potential as marker for preeclampsia. However, the cut-off may vary with gestational age and sensitivity and specificity need to be further investigated in larger cohorts. Disclosures K. Winkler: None. C. Contini: None. U. Pecks: None. M.M. Hoffmann: None. G. Putz: None.

Lipid profile in nonobese pregnant women with polycystic ovary syndrome: A prospective controlled clinical study

Alterations in lipid pattern and increased risk for obstetric/neonatal complications have been observed in patients with polycystic ovary syndrome (PCOS). Pregnancy leads to physiologic changes in lipoprotein metabolism, and alterations in lipid profile have been related with adverse pregnancy outcomes. Based on these considerations, the aim of the present prospective controlled clinical study was to test the hypothesis that the changes in the lipid profile in patients with PCOS during pregnancy are characteristic and potentially related to the increased risk of obstetric/neonatal complications. One hundred and fifty nonobese PCOS women and 150 age- and body mass index (BMI)-matched healthy controls were enrolled. Serum lipids, glucose, insulin, and androgens levels were serially assayed in all subjects before and throughout pregnancy. Serum low-density lipoprotein (LDL) and triglyceride (TG) concentrations were significantly (P<0.05) higher in PCOS group than in healthy controls at each assessment. Throughout pregnancy, serum LDL and TG levels increased significantly (P<0.05) in both groups, although the change from pre-pregnancy values was significantly (P<0.05) greater in PCOS patients than in healthy controls. A significant (P<0.05) relationship was observed between serum LDL and TG changes and changes in both insulin sensitivity indexes and androgen levels in PCOS patients alone. After adjusting for maternal age, pre-pregnancy BMI and lipid levels, body weight gain, and insulin-resistance markers, serum TG concentrations during pregnancy were directly and independently associated with obstetric complications in both groups, whereas serum LDL levels only in PCOS patients. We can conclude that nonobese PCOS patients had specific changes in lipid profile during pregnancy, and that the lipid pattern typical of PCOS may account for the more frequent adverse pregnancy outcomes. PCOS-related hormonal and metabolic features, such as insulin resistance and high androgen levels, may mediate this phenomenon.

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Applications of analysis of dynamic adaptations in parameter trajectories

Metabolic profiling in combination with pathway-based analyses and computational modelling are becoming increasingly important in clinical and preclinical research. Modelling multi-factorial, progressive diseases requires the integration of molecular data at the metabolome, proteome and transcriptome levels. Also the dynamic interaction of organs and tissues needs to be considered. The processes involved cover time scales that are several orders of magnitude different. We report applications of a computational approach to bridge the scales and different levels of biological detail. Analysis of dynamic adaptations in parameter trajectories (ADAPTs) aims to investigate phenotype transitions during disease development and after a therapeutic intervention. ADAPT is based on a time-dependent evolution of model parameters to describe the dynamics of metabolic adaptations. The progression of metabolic adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages. To get a better understanding of the concept, the ADAPT approach is illustrated in a theoretical study. Its application in research on progressive changes in lipoprotein metabolism is also discussed.

Severe hypertriglyceridemia

The Roundtable discussion in this issue is between the Editor and three experts in the diagnosis and management of severe hypertriglyceridemic conditions. In most patients, elevated triglycerides are a marker of increased cardiovascular disease risk related to multiple changes in lipoprotein metabolism that affect low-density lipoprotein (LDL) and high-density lipoprotein (HDL) as well as the triglyceride-rich very-low-density lipoprotein (VLDL) and chylomicrons. However, there are patients whose triglycerides are so high that signs and symptoms develop and indeed life-threatening disorders follow directly from the latter lipoproteins. Drs. John Brunzell, Robert Eckel, and Neil Stone are Professors of Medicine and expert lipidologists in institutions that have a volume of patients allowing a large experience over many years with severe hypertriglyceridemia. I am privileged to have them together to discuss this problem.

Serum paraoxonase-3 concentration in HIV-infected patients. Evidence for a protective role against oxidation

We investigated the influence of the HIV infection on serum paraoxonase-3 (PON3) concentration and assessed the relationships with lipoprotein-associated abnormalities, immunological response, and accelerated atherosclerosis. We studied 207 HIV-infected patients and 385 healthy volunteers. Serum PON3 was determined by in-house ELISA, and PON3 distribution in lipoproteins was investigated by fast-performance liquid chromatography (FPLC). Polymorphisms of the PON3 promoter were analyzed by the Iplex Gold MassArray(TM) method. PON3 concentrations were increased (about three times) in HIV-infected patients with respect to controls (P < 0.001) and were inversely correlated with oxidized LDL levels (P = 0.038). Long-term use of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy was associated with a decrease of PON3 concentrations. In a multivariate linear regression analysis, these relationships were still strong when the main confounding covariates were considered. PON3 was mainly found in HDL in HIV-infected patients, but a substantial amount of the protein was detected in LDL particles. This study reports for the first time an important increase in serum PON3 concentrations in HIV-infected patients that is associated with their oxidative status and their treatment with NNRTI. Long-term, prospective studies are needed to confirm the possible influence of this enzyme on the course of this disease and its possible utility as an analytical biomarker.

A Differential Network Approach to Exploring Differences between Biological States: An Application to Prediabetes

BackgroundVariations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation.MethodologyHere, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data on lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes.Conclusions/SignificanceDifferential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches.