Novel Therapeutic Approaches for the Management of Elevated Lipoprotein(a): From Traditional Agents to Future Treatment Options.

Cardiovascular disease is the leading cause of mortality worldwide. Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering agents, an increased cardiovascular risk is still observed in individuals with therapeutic LDL-C levels. One of these cardiovascular risk factors is elevated plasma lipoprotein(a) (Lp(a)) concentration, which maintains chronic inflammation through the increased presence of oxidized phospholipids on its surface. In addition, due to its 90 percent homology with the fibrinolytic proenzyme plasminogen, Lp(a) exhibits atherothrombotic effects. These may also contribute to the increased cardiovascular risk in individuals with high Lp(a) levels that previous epidemiological studies have shown to exist independently of LDL-C and other lipid parameters. In this review, the authors overview the novel therapeutic options to achieve effective Lp(a) lowering treatment, which may help to define tailored personalized medicine and reduce the residual cardiovascular risk in high-risk patients. Agents that increase LDL receptor expression, including statins, proprotein convertase subtilisin kexin type 9 inhibitors, and LDL production inhibitors, are also discussed. Other treatment options, e.g., cholesterolester transfer protein inhibitors, nicotinic acid derivatives, thyroid hormone mimetics, lipoprotein apheresis, as well as apolipoprotein(a) reducing antisense oligonucleotides and small interfering RNAs, are also evaluated.

Effectiveness of hospital-based low intensity and inspected aerobic training on functionality and cardiorespiratory fitness in unconditioned stroke patients: Importance of submaximal aerobic fitness markers.

INTRODUCTION: The purpose of our study was to evaluate the effectiveness of low-to moderate intensity aerobic training on cardiorespiratory functions in chronic unconditioned stroke patients. The oxygen uptake efficiency slope (OUES) and the ventilatory threshold (VO2-VT) could represent the aerobic capacity in submaximal test. Our study examined the application of the submaximal parameters for evaluating aerobic capacity of chronic stroke patients. MATERIALS AND METHODS: In our assessor-blinded controlled pilot study 37 patients were randomized into 2 groups named: intervention group (IG, n: 21) and control group (CG, n:16), respectively. Cardiorespiratory functions were evaluated by ergospirometer before and after the 4-week (20 days) program. Both groups participated in daily occupational therapy (30 minutes) and conventional, customized physiotherapy CG (60 minutes), IG (30 minutes). Only IG performed aerobic training by bicycles (30 minutes) aiming to reach low-to moderate training intensity. Outcome measures included peak oxygen uptake (VO2 peak), OUES, VO2-VT, functional exercise capacity 6-Minute Walking Test (6MWT) and Functional Independence Measure. RESULTS: Thirty-five subjects completed the study. The VO2 peak uptake was very low in both groups (IG: 11.9 mL/kg/min, CG: 12.45 mL/kg/min) and did not improve after the program, but submaximal parameters such as VO2-VT (P < .01) and OUES (P < .001) have shown significant improvement, but only in IG regardless of insufficient impact on VO2 peak. Each participant in both groups was unable to permanently reach the moderate intensity zone. Functional Independence Measure changed for the better in both groups, but 6MWT only in the IG. DISCUSSION AND CONCLUSIONS: Four-week exercise training even at low intensity by lower limb cycle ergometer may provide benefit on aerobic and functional capacity without improvement of VO2 peak on unconditioned chronic stroke patients.

Identifying Patients with Familial Chylomicronemia Syndrome Using FCS Score-Based Data Mining Methods.

BACKGROUND: There are no exact data about the prevalence of familial chylomicronemia syndrome (FCS) in Central Europe. We aimed to identify FCS patients using either the FCS score proposed by Moulin et al. or with data mining, and assessed the diagnostic applicability of the FCS score. METHODS: Analyzing medical records of 1,342,124 patients, the FCS score of each patient was calculated. Based on the data of previously diagnosed FCS patients, we trained machine learning models to identify other features that may improve FCS score calculation. RESULTS: We identified 26 patients with an FCS score of ≥10. From the trained models, boosting tree models and support vector machines performed the best for patient recognition with overall AUC above 0.95, while artificial neural networks accomplished above 0.8, indicating less efficacy. We identified laboratory features that can be considered as additions to the FCS score calculation. CONCLUSIONS: The estimated prevalence of FCS was 19.4 per million in our region, which exceeds the prevalence data of other European countries. Analysis of larger regional and country-wide data might increase the number of FCS cases. Although FCS score is an excellent tool in identifying potential FCS patients, consideration of some other features may improve its accuracy.

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning.

Background and aims: Premature mortality due to atherosclerotic vascular disease is very high in Hungary in comparison with international prevalence rates, though the estimated prevalence of familial hypercholesterolemia (FH) is in line with the data of other European countries. Previous studies have shown that high lipoprotein(a)- Lp(a) levels are associated with an increased risk of atherosclerotic vascular diseases in patients with FH. We aimed to assess the associations of serum Lp(a) levels and such vascular diseases in FH using data mining methods and machine learning techniques in the Northern Great Plain region of Hungary. Methods: Medical records of 590,500 patients were included in our study. Based on the data from previously diagnosed FH patients using the Dutch Lipid Clinic Network scores (≥7 was evaluated as probable or definite FH), we trained machine learning models to identify FH patients. Results: We identified 459 patients with FH and 221 of them had data available on Lp(a). Patients with FH had significantly higher Lp(a) levels compared to non-FH subjects [236 (92.5; 698.5) vs. 167 (80.2; 431.5) mg/L, p < .01]. Also 35.3% of FH patients had Lp(a) levels >500 mg/L. Atherosclerotic complications were significantly more frequent in FH patients compared to patients without FH (46.6 vs. 13.9%). However, contrary to several other previous studies, we could not find significant associations between serum Lp(a) levels and atherosclerotic vascular diseases in the studied Hungarian FH patient group. Conclusion: The extremely high burden of vascular disease is mainly explained by the unhealthy lifestyle of our patients (i.e., high prevalence of smoking, unhealthy diet and physical inactivity resulting in obesity and hypertension). The lack of associations between serum Lp(a) levels and atherosclerotic vascular diseases in Hungarian FH patients may be due to the high prevalence of these risk factors, that mask the deleterious effect of Lp(a).

Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia.

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions.

Smoothelin-Like Protein 1 Regulates Development and Metabolic Transformation of Skeletal Muscle in Hyperthyroidism.

Hyperthyroidism triggers a glycolytic shift in skeletal muscle (SKM) by altering the expression of metabolic proteins, which is often accompanied by peripheral insulin resistance. Our previous results show that smoothelin-like protein 1 (SMTNL1), a transcriptional co-regulator, promotes insulin sensitivity in SKM. Our aim was to elucidate the role of SMTNL1 in SKM under physiological and pathological 3,3',5-Triiodo-L-thyronine (T3) concentrations. Human hyper- and euthyroid SKM biopsies were used for microarray analysis and proteome profiler arrays. Expression of genes related to energy production, nucleic acid- and lipid metabolism was changed significantly in hyperthyroid samples. The phosphorylation levels and activity of AMPKα2 and JNK were increased by 15% and 23%, respectively, in the hyperthyroid samples compared to control. Moreover, SMTNL1 expression showed a 6-fold decrease in the hyperthyroid samples and in T3-treated C2C12 cells. Physiological and supraphysiological concentrations of T3 were applied on differentiated C2C12 cells upon SMTNL1 overexpression to assess the activity and expression level of the elements of thyroid hormone signaling, insulin signaling and glucose metabolism. Our results demonstrate that SMTNL1 selectively regulated TRα expression. Overexpression of SMTNL1 induced insulin sensitivity through the inhibition of JNK activity by 40% and hampered the non-genomic effects of T3 by decreasing the activity of ERK1/2 through PKCδ. SMTNL1 overexpression reduced IRS1 Ser307 and Ser612 phosphorylation by 52% and 53%, respectively, in hyperthyroid model to restore the normal responsiveness of glucose transport to insulin. SMTNL1 regulated glucose phosphorylation and balances glycolysis and glycogen synthesis via the downregulation of hexokinase II by 1.3-fold. Additionally, mitochondrial respiration and glycolysis were measured by SeaHorse analysis to determine cellular metabolic function/phenotype of our model system in real-time. T3 overload strongly increased the rate of acidification and a shift to glycolysis, while SMTNL1 overexpression antagonizes the T3 effects. These lines of evidence suggest that SMTNL1 potentially prevents hyperthyroidism-induced changes in SKM, and it holds great promise as a novel therapeutic target in insulin resistance.

An ω-3, but Not an ω-6 Polyunsaturated Fatty Acid Decreases Membrane Dipole Potential and Stimulates Endo-Lysosomal Escape of Penetratin.

Although the largely positive intramembrane dipole potential (DP) may substantially influence the function of transmembrane proteins, its investigation is deeply hampered by the lack of measurement techniques suitable for high-throughput examination of living cells. Here, we describe a novel emission ratiometric flow cytometry method based on F66, a 3-hydroxiflavon derivative, and demonstrate that 6-ketocholestanol, cholesterol and 7-dehydrocholesterol, saturated stearic acid (SA) and ω-6 γ-linolenic acid (GLA) increase, while ω-3 α-linolenic acid (ALA) decreases the DP. These changes do not correlate with alterations in cell viability or membrane fluidity. Pretreatment with ALA counteracts, while SA or GLA enhances cholesterol-induced DP elevations. Furthermore, ALA (but not SA or GLA) increases endo-lysosomal escape of penetratin, a cell-penetrating peptide. In summary, we have developed a novel method to measure DP in large quantities of individual living cells and propose ALA as a physiological DP lowering agent facilitating cytoplasmic entry of penetratin.

The effect of low-intensity aerobic training on cognitive functions of severely deconditioned subacute and chronic stroke patients: a randomized, controlled pilot study.

Our objective was to investigate the impact of low-intensity aerobic training on cognitive functions in severely deconditioned subacute and chronic stroke patients. For this purpose, a randomized, controlled pilot study was designed involving subacute and chronic stroke patients. Thirty-seven eligible patients participated in the 4-week-long randomized, controlled pilot study. Patients were randomized into study group and control group and both groups participated in conventional physiotherapy included occupational therapy. Only the study group's patients participated in a low-intensity aerobic training by cycle ergometer. Cognitive evaluations (Functional Independence Measure Cognitive part - FIM-cog; Coding and Symbol Search tasks of the Processing Speed index and Digit Span task of Working Memory index of Wechsler Adult Intelligence Scale-Fourth Edition) were performed before and after the programme. In-group analysis showed a significant improvement in study group patients regarding Coding subtest of Processing Speed domain (P = 0.003). Symbol Search subtest of Processing Speed showed significant improvements in both groups by the end of the programme (study group, P = 0.041; control group, P = 0.006). There were no significant changes in the FIM-cog and Digit Span task. The intergroup analysis did not find significant difference between the two groups. It was concluded that even the low-intensity aerobic training may improve special domains of cognitive function after stroke. Further studies are needed to confirm the impact of low-intensity aerobic training on cognitive functions.

Identifying patients with familial hypercholesterolemia using data mining methods in the Northern Great Plain region of Hungary.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is one of the most frequent diseases with monogenic inheritance. Previous data indicated that the heterozygous form occurred in 1:250 people. Based on these reports, around 36,000-40,000 people are estimated to have FH in Hungary, however, there are no exact data about the frequency of the disease in our country. Therefore, we initiated a cooperation with a clinical site partner company that provides modern data mining methods, on the basis of medical and statistical records, and we applied them to two major hospitals in the Northern Great Plain region of Hungary to find patients with a possible diagnosis of FH. METHODS: Medical records of 1,342,124 patients were included in our study. From the mined data, we calculated Dutch Lipid Clinic Network (DLCN) scores for each patient and grouped them according to the criteria to assess the likelihood of the diagnosis of FH. We also calculated the mean lipid levels before the diagnosis and treatment. RESULTS: We identified 225 patients with a DLCN score of 6-8 (mean total cholesterol: 9.38 ±â€¯3.0 mmol/L, mean LDL-C: 7.61 ±â€¯2.4 mmol/L), and 11,706 patients with a DLCN score of 3-5 (mean total cholesterol: 7.34 ±â€¯1.2 mmol/L, mean LDL-C: 5.26 ±â€¯0.8 mmol/L). CONCLUSIONS: The analysis of more regional and country-wide data and more frequent measurements of total cholesterol and LDL-C levels would increase the number of FH cases discovered. Data mining seems to be ideal for filtering and screening of FH in Hungary.

Plasminogen Activator Inhibitor-1 Level Correlates with Lipoprotein Subfractions in Obese Nondiabetic Subjects.

BACKGROUND: The elevated level of plasminogen activator inhibitor-1 (PAI-1) in obese subjects with metabolic syndrome and in patients with type 2 diabetes is well established. The association of plasma PAI-1 and lipid metabolism is still unclear. The aim of the present study was to determine the relationship between plasma PAI-1 levels and the distribution of lipoprotein subfractions in obese and lean nondiabetic individuals. SUBJECTS AND METHODS: We enrolled fifty nondiabetic obese patients and thirty-two healthy volunteers. Lipoprotein subfractions were detected with Lipoprint System. Plasma PAI-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and myeloperoxidase (MPO) concentrations were determined with enzyme-linked immunosorbent assay (ELISA), while serum paraoxonase-1 (PON1) activities were measured by spectrophotometry. RESULTS: The TNF-α, IL-6, oxidized low-density lipoprotein (oxLDL), and MPO levels were found to be significantly higher, while PON1 paraoxonase and arylesterase activities were nonsignificantly lower in the obese patients. Strong significant negative correlations were found between plasma PAI-1 concentration and mean LDL size, as well as between PAI-1 concentrations and the levels of the large and intermediate high-density lipoprotein (HDL) subfractions. In multiple regression analysis, PAI-1 was predicted by waist circumference and intermediate HDL subfraction. CONCLUSION: The significant correlations between PAI-1 levels and lipoprotein subfractions indicate the link between PAI-1 and lipid metabolism in obesity.

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia.

BACKGROUND: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. PATIENTS AND METHODS: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. RESULTS: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. CONCLUSIONS: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Impact of selective LDL apheresis on serum chemerin levels in patients with hypercholesterolemia.

BACKGROUND: Selective low-density lipoprotein (LDL) apheresis is commonly used to treat patients with familial hypercholesterolemia (FH). Chemerin is an adipokine with putative roles in the regulation of lipid metabolism. METHODS: In our pilot study, we measured serum chemerin levels by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments using the technique of direct adsorption of lipoproteins (DALI). RESULTS: The first treatment sessions decreased serum chemerin levels by an average of 27.26 %. While following one patient, 12 months of regular LDL apheresis resulted in a permanent reduction in his serum chemerin level. Changes in the lipoprotein subfractions measured by gel electrophoresis (Lipoprint) correlated with the reduction of chemerin levels. Furthermore, we eluted and then measured chemerin bound to the DALI column. CONCLUSION: We conclude that LDL apheresis decreases the circulating level of chemerin by binding the protein to the column and thus improves lipoprotein subfraction pattern.

Changes in triglyceride, HDL-C, and non-HDL-C levels in patients with acute coronary syndrome.

BACKGROUND: Changes in high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels have been linked to residual cardiovascular risk, whereas non-HDL-C levels have been shown to be more predictive of cardiovascular risk than are low-density lipoprotein cholesterol (LDL-C) levels. We aimed to investigate the impact of HDL-C, TG, and non-HDL-C levels on acute coronary syndrome (ACS) risk with on-target LDL-C levels. METHODS: In all, 424 Caucasian patients aged over 50 years who had LDL-C levels below 3.4 mmol/l with a first or subsequent ACS event were enrolled in a multicenter, retrospective study. Lipid samples were collected within 4 days after the cardiovascular event. The subjects of the age-matched, gender-balanced control group (n = 443) had LDL-C levels below 3.4 mmol/l and were free of cardiovascular diseases. RESULTS: Patients with ACS had significantly higher TG and lower HDL-C levels compared with the control patients; however, we did not find any significant difference regarding non-HDL-C levels between the two groups. In regression analysis, the risk of coronary heart disease increased significantly with 1 standard deviation (SD) increase in TG and 1 SD decrease in HDL-C levels. CONCLUSION: High TG and low HDL-C levels may contribute to residual cardiovascular risk in patients with well-controlled LDL-C levels; however, non-HDL-C levels at admission did not seem to be predictive for patients with ACS. Detection and treatment of secondary lipid targets such as high TG and low HDL-C levels may be important for the prevention of cardiovascular diseases.

Paraoxonase-1 arylesterase activity is an independent predictor of myeloperoxidase levels in overweight patients with or without cardiovascular complications.

OBJECTIVES: Myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were shown to contribute to atherogenesis, while human paraoxonase-1 (PON1) protects against oxidative stress. Although several studies investigated these biomarkers, their associations have not been completely clarified yet. We aimed to investigate these parameters in overweight hyperlipidemic, lipid-lowering therapy-naive patients (n=167) with and without vascular complications. DESIGN AND METHODS: MPO, MMP-9 and TIMP-1 levels were measured by ELISA. PON1 activities were detected spectrophotometrically. PON1 phenotype was calculated by using a dual substrate method. RESULTS: Patients with vascular complications (VC) had significantly higher MPO and TIMP-1 levels compared to those without (patients with no vascular complications; NVC) (728 (367.25-1177.90) mg/ml vs. 315.9 (176.05-687.40) mg/ml; p<0.001; and 172.7 (157.7-197.7) ng/ml vs. 152.6 (129.3-172.3) ng/ml; p<0.0001; respectively). MPO levels showed a significant negative correlation with PON1 arylesterase activity (whole patient group (W): r=0.42, p<0.0001; VC: r=0.44, p=0.01; NVC: r=0.39, p<0.0001) and positive correlations with MMP-9 (W: r=0.37, p<0.0001; VC: r=0.29, p=0.07; NVC: r=0.42, p<0.0001) and TIMP-1 (W: r=0.42, p<0.0001; VC: r=0.33, p<0.05; NVC: r=0.41, p<0.0001), respectively. PON1 arylesterase activity was found to be an independent predictor of MPO levels in the whole patient group (ß=-0.350, p<0.0001) or when studied separately in the subgroups with or without cardiovascular complications (VC: ß=-0.57, p<0.05; NVC: ß=-0.33, p<0.0001). CONCLUSIONS: Our results suggest that parallel investigation of MPO, MMP-9 and TIMP-1 levels and PON1 arylesterase activity may be a more accurate indicator of atherosclerosis, which may allow earlier treatment and therefore, improvement of treatment efficacy.

Paraoxonase-1 and adipokines: Potential links between obesity and atherosclerosis.

Oxidative stress and chronic low-grade inflammation are major characteristics of obesity-related disorders. The dominance of pro-oxidant and pro-inflammatory mechanisms triggers insulin resistance and enhances the progression of atherosclerosis. Discovered first as an esterase that hydrolyze organophosphates, human paraoxonase-1 is bound to high-density lipoprotein and inhibits the oxidation of lipoproteins and reduces the degree of inflammation, hence it is considered to act against atherosclerosis. In contrast, the majority of the adipokines secreted from the enlarged white adipose tissue promote the atherosclerotic process; and altered adipokine secretion is now regarded as one of the major contributors of increased cardiovascular morbidity and mortality in obesity. In this review, we detail the correlations between paraoxonase-1 and some selected adipokines, namely leptin, adiponectin and chemerin. Adipokine imbalance leads to decreased paraoxonase-1 activity that results in enhanced atherosclerosis; therefore, altered adipokine secretion may be predictive of cardiovascular complications in obesity. As an active organ secreting biological active substances, white adipose tissue may also act as a "fine-tuner" of immune and endocrine actions attenuating or enhancing reactions triggered by pathogens, inflammation and metabolic stimuli; and obesity, as a chronic noxious state may perturb the proper functioning of this fine-tuning process. Further investigations are of major importance to elucidate the associations between adipokines and paraoxonase-1 and to establish accurate interventions against obesity-related disorders.

High-density lipopoprotein antioxidant capacity, subpopulation distribution and paraoxonase-1 activity in patients with systemic lupus erythematosus.

BACKGROUND: The causes of increased cardiovascular risk in systemic lupus erythematosus (SLE) are not understood thoroughly, although presence of traditional cardiovascular risk factors and disease-specific agents were also proposed. In this study, we investigated the quantitative changes in the lipid profile, as well as qualitative characteristics of high-density lipoprotein (HDL) and markers of inflammation and disease activity in SLE patients. METHODS: Lipoprotein levels were determined in 51 SLE patients and 49 healthy controls, matched in age and gender. HDL antioxidant capacity was determined spectrophotometrically with a cell-free method of hemin-induced low-density lipoprotein (LDL) oxidation. Polyacrylamide gel-electrophoresis was used for HDL subfraction analysis. Human paraoxonase-1 (PON1) activity, apolipoprotein A1 (ApoA1) and oxidized LDL concentrations, as well as interleukin-6, high-sensitivity C-reactive protein, serum amyloid A and monocyte chemotactic protein-1 levels were determined. RESULTS: HDL-cholesterol and ApoA1 concentrations decreased significantly in SLE subjects. Also, PON1 arylesterase activity (125.65 ± 26.87 vs. 148.35 ± 39.34 U/L, p = 0.001) and total HDL antioxidant capacity (165.82 ± 58.28% vs. 217.71 ± 54.36%, p < 0.001) were significantly reduced in patients compared to controls. Additionally, all HDL subfraction concentrations were significantly decreased in patients, while the levels of the examined inflammatory markers were significantly elevated in SLE subjects. The latter correlated positively with disease activity, and negatively with HDL concentration and total HDL antioxidant capacity, respectively. PON1 arylesterase activity and erythrocyte sedimentation rate were independent predictors of total HDL antioxidant capacity. CONCLUSIONS: Induced by the systemic inflammation, altered composition and antioxidant activity may diminish the anti-atherogenic effect of HDL and therefore may contribute to the increased cardiovascular risk of SLE patients.

Altered lipid subfraction profile and impaired antioxidant defense of high-density lipoprotein in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a rare disease caused by biallelic mutation in the 7-dehydrocholesterol (7DHC) reductase gene. High oxidizability of 7DHC and the appearance of small-sized low-density lipoprotein (LDL) subfractions indicate increased endogenous oxidative stress that is counterbalanced by natural antioxidant defense mechanisms including the high-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) enzyme. PON1 prevents lipoproteins from oxidative modifications; however, PON1 activity and the distribution of lipoprotein subfractions have not been studied in SLOS. METHODS: 7DHC levels and PON1 arylesterase activities were measured spectrophotometrically in 11 SLOS patients and 10 healthy children. Lipoprotein subfractions were detected by polyacrylamide gel electrophoresis. RESULTS: Compared to controls, there was a shift towards the small-dense LDL subfraction and the large HDL subfraction in SLOS. PON1 arylesterase activity was significantly decreased in SLOS patients and correlated negatively with the proportion of small-dense LDL subfraction and the proportion of large HDL subfraction. Significant positive correlations were detected between PON1 arylesterase activity and the ratios of intermediate and small HDL subfractions. CONCLUSIONS: Decreased PON1 activity and the deleterious shift in the distribution of lipoprotein subfractions may contribute to the impaired antioxidant status observed in SLOS. Monitoring of serum PON1 arylesterase activity may be a complementary biomarker in SLOS.

Dynamic interplay between metabolic syndrome and immunity.

Obesity and its co-morbidities as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases are major health problems worldwide. Several reports indicated that nutrient excess and metabolic syndrome are linked with altered immune response. Indeed, metabolic syndrome is characterized by insulin resistance and chronic low-grade inflammation, which conditions are the consequences of the complex interaction between adipocytes and immune cells. Enlarged white adipose tissue is infiltrated by immune cells and secretes various bioactive substances, like adipokines, cytokines and other inflammatory mediators. Due to its special architecture in which metabolic and immune cells are in intimate proximity, metabolic and immunologic pathways are closely integrated in adipose tissue. With the contribution of altered gut microbiota, adipokines and cytokines modulate insulin signaling and immune response leading to adipose tissue inflammation and systemic insulin resistance. In this chapter, we focus on the cellular and molecular mechanisms that lead to impaired insulin sensitivity and chronic low-grade inflammation in obesity. We also detail the potential role of adipokines and immune cells in this deleterious process, and the concerns of vaccination in metabolic syndrome. Finally, we address the links between obesity and gut microbiota as an emerging new field of interest, and scratch the surface of potential therapeutic opportunities.

Association of chemerin with oxidative stress, inflammation and classical adipokines in non-diabetic obese patients.

The prevalence of obesity has been increasing worldwide. Chemerin is a recently discovered adipokine secreted by the enlarged adipose tissue with diverse biological effects that are not well detailed yet. This study aimed to elucidate the potential role of chemerin in oxidative stress and inflammation that are characteristics for excess weight and may eventually lead to insulin resistance and atherosclerotic complications. We also analysed the associations between chemerin and classical adipokines, namely leptin and adiponectin. Therefore, we investigated non-diabetic obese patients without manifest cardiovascular disease and compared their data to healthy lean individuals. Chemerin correlated positively with markers of oxidative stress and inflammation, while it showed a negative correlation with the measure of antioxidant status, characterized by the HDL-linked paraoxonase-1 enzyme. Chemerin also correlated positively with leptin and negatively with adiponectin respectively. In our study population, oxidized low-density lipoprotein and high-sensitivity C-reactive protein were found to be the strongest predictors of chemerin level. We conclude that chemerin may contribute to chronic inflammation and increased oxidative stress in obese individuals, even in the absence of manifest insulin resistance.

Strong correlations between circulating chemerin levels and lipoprotein subfractions in nondiabetic obese and nonobese subjects.

OBJECTIVE: Chemerin is a recently described adipokine expressed primarily in the white adipose tissue. Compared with lean subjects, circulating chemerin levels are significantly elevated in obese individuals and correlate positively with the prevalence of various cardiovascular risk factors including altered lipoprotein levels. To date, the impact of chemerin on lipoprotein subfractions and its role in atherosclerotic processes are still unclear. PATIENTS AND METHODS: Fifty nondiabetic obese (NDO) patients and 38 lean controls matched in age and gender were enrolled. Chemerin level was measured by ELISA. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions were detected by nongradient polyacrylamide gel electrophoresis (Lipoprint). RESULTS: We detected significantly higher serum chemerin levels in NDO patients compared with healthy controls (590·1 ± 190·3 ng/ml vs 405 ± 127·1 ng/ml, P < 0·001). A significant positive correlation was found between chemerin and LDL cholesterol levels, while chemerin showed a significant negative correlation with the level of HDL cholesterol. Significant positive correlation was detected between chemerin and the ratio of small dense LDL, while chemerin correlated negatively with the mean LDL size. Also, a significant negative correlation was found between serum chemerin and the ratio of large HDL subfraction, while there were significant positive correlations between chemerin levels and intermediate and small HDL subfraction ratios, respectively. CONCLUSION: Chemerin may be involved in the regulation of lipoprotein metabolism in obese patients who do not show apparent abnormalities of glucose metabolism. Early changes in the distribution of the lipoprotein subfractions may contribute to the progression of atherosclerosis, leading to increased cardiovascular risk.