Impaired Reverse Cholesterol Transport is Associated with Changes in Fatty Acid Profile in Children and Adolescents with Abdominal Obesity.

BACKGROUND: Abdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. OBJECTIVES: Our aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. METHODS: Seventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. RESULTS: The obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). CONCLUSIONS: Children and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk.

Sweet swell of burning fat: emerging role of high-density lipoprotein in energy homeostasis.

PURPOSE OF REVIEW: Metabolism of lipids and lipoproteins, including high-density lipoprotein (HDL), plays a central role in energy homeostasis. Mechanisms underlying the relationship between energy homeostasis and HDL however remain poorly studied. RECENT FINDINGS: Available evidence reveals that HDL is implicated in energy homeostasis. Circulating high-density lipoprotein-cholesterol (HDL-C) levels are affected by energy production, raising with increasing resting metabolic rate. Lipolysis of triglycerides as a source of energy decreases plasma levels of remnant cholesterol, increases levels of HDL-C, and can be cardioprotective. Switch to preferential energy production from carbohydrates exerts opposite effects. SUMMARY: Low HDL-C may represent a biomarker of inefficient energy production from fats. HDL-C-raising can be beneficial when it reflects enhanced energy production from burning fat.

Impaired HDL-associated enzymes and proteins in children and adolescents with weight disorders and their association with novel cardiometabolic indexes.

BACKGROUND AND AIMS: Overweight/obesity (OW/OB) is associated with modifications in lipoprotein (Lp)-associated enzymes and proteins, such as cholesteryl ester transfer protein (CETP), Lp-associated phospholipase A2 (LpPLA2) and paraoxonase (PON)1. No evidence is available regarding underweight (UW). The following indexes have been proposed to better assess atherogenic risk related to weight alterations: triglycerides-glucose index (TyG), visceral adiposity index (VAI) and height-corrected lipid accumulation product (HLAP). AIM: To analyze the presence of alterations in Lp-associated enzymes and proteins in children and adolescents with UW and OW/OB and their relation to novel cardiometabolic indexes. METHODS AND RESULTS: Thirty male children and adolescents with UW, 66 with normal weight (NW) and 30 with OW/OB were included. Anthropometric parameters, glucose, Lp profile and the activities of CETP, LpPLA2 and PON1 were evaluated. Body mass index (BMI)-z, TyG, VAI and HLAP were calculated. UW and NW showed lower CETP activity than OW/OB (Mean ± SD) (218 ± 38vs.224 ± 26vs.237 ± 26%/mL.h; p < 0.05). UW and OW/OB showed lower PON1 activity than NW (318 ± 170vs.409 ± 200vs.310 ± 184 nmol/mL.min; p < 0.05). TyG was higher in OW/OB than UW (p < 0.01), whilst both HLAP (p < 0.05) and VAI (p < 0.01) followed a linear trend across weight categories. After adjusting for age and BMI-z, TyG was an independent predictor of CETP (r2 = 0.25, ß = -0.22, p < 0.01) and LpPLA2 (r2 = 0.21,ß = -0.21,p < 0.05), while VAI (r2 = 0.21,ß = -0.32,p < 0.01) and HLAP (r2 = 0.20,ß = -0.31,p < 0.01) of CETP. CONCLUSIONS: Both UW and OW/OB showed impaired antioxidant PON1 activity. Moreover, TyG, VAI and HLAP were all capable of predicting alterations in crucial modulators of Lp metabolism and vascular inflammation in children and adolescents with varying degrees of alterations in body weight.

Vascular inflammation and impaired reverse cholesterol transport and lipid metabolism in obese children and adolescents.

BACKGROUND AND AIMS: Childhood obesity is associated to complications such as insulin resistance and dyslipidemia. High density lipoproteins (HDL) constitute the only lipoprotein fraction with ateroprotective properties. The aim of the present study was to analyze inflammatory markers, carbohydrate metabolism, lipid profile and HDL functionality in obese children and adolescents compared to healthy controls. METHODS AND RESULTS: Twenty obese children and adolescents (Body mass index z score >3.0) (9-15 years old) and 20 age and sex similar controls were included in the study. Triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C, apolipoproteins (apo) A-I and B, glucose and insulin levels were quantified. Lipid indexes and HOMA-IR were calculated. Cholesterol efflux (CEC), lipoprotein associated phospholipase A2 (Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein, plus paraoxonase and arylesterase (ARE) activities were evaluated. Obese children and adolescents showed significantly higher TG [69 (45-95) vs 96 (76-121); p < 0.05], non-HDL-C [99 ± 34 vs 128 ± 26; p < 0.01], TC/HDL-C [2.8 ± 0.6 vs 4.7 ± 1.5; p < 0.01], TG/HDL-C [1.1 (1.0-1.8) vs 2,2 (1.4-3.2); p < 0.01], and HOMA-IR [1.5 (1.1-1.9) vs. 2.6 (2.0-4.5); p < 0.01] values, plus Lp-PLA2 activity [8.3 ± 1.9 vs 7.1 ± 1.7 umol/ml.h; p < 0,05] in addition to lower HDL-C [57 ± 10 vs 39 ± 9; p < 0.01], apo A-I [143 ± 25 vs 125 ± 19; p < 0.05], and CEC [6.4 (5.1-6.8) vs. 7.8 (5.7-9.5); p < 0.01] plus LCAT [12.6 ± 3.3 vs 18.7 ± 2.6; p < 0.05] and ARE [96 ± 19 vs. 110 ± 19; p < 0.05] activities. Lp-PLA2 activity correlated with LDL-C (r = 0.72,p < 0.01), non-HDL-C (r = 0.76,p < 0.01), and apo B (r = 0.60,p < 0.01). LCAT activity correlated with triglycerides (r = -0.78,p < 0.01), HDL-C (r = 0.64,p < 0.01), and apo A-I (r = 0.62, p < 0.05). ARE activity correlated with HDL-C (r = 0.32,p < 0.05) and apoA-I (r = 0.43,p < 0.01). CEC was negatively associated with BMI z-score (r = -0.36,p < 0.05), and triglycerides (r = -0.28,p < 0.05), and positively with LCAT activity (r = 0.65,p < 0.05). In multivariate analysis, BMI z-score was the only parameter significantly associated to CEC (r2 = 0.43, beta = -0.38, p < 0.05). CONCLUSION: The obese group showed alterations in carbohydrate and lipid metabolism, which were associated to the presence of vascular specific inflammation and impairment of HDL atheroprotective capacity. These children and adolescents would present qualitative alterations in their lipoproteins which would determine higher risk of suffering premature cardiovascular disease.

Hazardous effects of urban air particulate matter acute exposure on lung and extrapulmonary organs in mice.

Air particulate matter (PM) can lead to extrapulmonary adverse reactions in organs such as liver and heart either by particle translocation from the lung to the systemic circulation or by the release of lung mediators. Young BALB/c mice were intranasal instilled with 1mg/BW of Urban Air Particles from Buenos Aires or Residual Oil Fly Ash. Histopathology, oxidative metabolism and inflammation on lungs and extrapulmonary organs and the systemic response were evaluated. Lung histophatological analysis supported the rise in the number of inflammatory cells in the bronchoalveolar lavage from PM-exposed animals. Also, both PM caused recruitment of inflammatory cells in the liver and heart parenchyma and IL-6 and transaminases augmentation in serum. We have shown that despite morphochemical differences, both urban air PM altered the lung and extrapulmonary organs. Therefore, exposure to urban air PM may distress body metabolism which, in turn could lead to the development and progression of multifactorial diseases.

- 174 G>C IL-6 polymorphism and primary iron overload in male patients.

Primary iron overload (IO) is commonly associated with mutations in the hereditary hemochromatosis gene (HFE). Nonetheless, other genetic variants may influence the development of IO beyond HFE mutations. There is a single nucleotide polymorphism (SNP) at - 174 G>C of the interleukin (IL)-6 gene which might be associated with primary IO. Our aim was to study the association between the SNP - 174 G>C gene promoter of IL-6 and primary IO in middle-aged male patients. We studied 37 men with primary IO diagnosed by liver histology. Controls were age-matched male volunteers (n = 37). HFE mutations and the SNP - 174 G>C gene promoter of IL-6 were evaluated by PCR-RFLP. Logistic regression was used to evaluate the association between primary IO and SNP - 174 G>C gene promoter of IL-6. Patients and control subjects were in Hardy-Weinberg equilibrium for the SNP - 174 G>C gene promoter of IL-6 (p = 0.17). Significantly different genotype frequencies were observed between patients (43% CC, 43% CG, and 14% GG) and control subjects (10% CC, 41% CG, and 49% GG) (OR = 4.09, 95% CI = 2.06-8.13; p < 0.0001). The multiple logistic regression analysis showed that IO was significantly associated with CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 (OR = 6.3, 95% CI = 1.9-21.4; p < 0.005) in a model adjusted by age and body mass index. In conclusion, CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 can be proposed as one of the gene variants influencing iron accumulation in male adults with HFE mutations. Studies in larger cohorts are warranted.

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c.

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.

Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.

Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced ß-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.

CONDITIONING FACTORS FOR HIGH CARDIOVASCULAR RISK IN PATIENTS WITH CUSHING SYNDROME.

OBJECTIVE: To characterize the alterations in carbohydrate and lipoprotein metabolism, to evaluate markers of lipoprotein functionality, and to identify the presence of novel atherogenic risk factors in patients with Cushing syndrome (CS) in comparison with sex- and age-matched controls. METHODS: In an open, cross-sectional study, 32 nontreated patients with active CS were consecutively recruited from the Endocrinology Service at "José de San Martín" Clinical Hospital, University of Buenos Aires, Argentina, between April 11, 2010 and December 11, 2012. The patients were compared with sex- and age-matched controls. RESULTS: Versus controls, patients with CS presented with excess weight, central obesity, and hypercortisolism. They also exhibited an insulin-resistant state, with high resistin levels (median [interquartile range], 16 [10 to 22] ng/mL versus 6 [5 to 9] ng/mL; P<.0001), a more atherogenic lipoprotein profile, high oxidized low-density lipoprotein levels (oxLDL; mean ± SD, 100 ± 31 U/L versus 75 ± 32 U/L; P<.05) and high sensitive C-reactive protein levels (median [interquartile range], 1.2 [0.6 to 3.1] mg/L versus 0.6 [0.3 to 1.1] mg/L; P<.05), and increased leukocyte count (mean ± SD, 9.5 ± 2.6 × 10(3) cells/µL versus 6.5 ± 1.4 × 10(3) cells/µL; P<.0001). Multivariate analyses showed that the increase in waist circumference was associated with both the diagnosis of CS and the degree of insulin resistance. Resistin concentration was related to a greater extent to the diagnosis of CS than to homeostasis model assessment-insulin resistance. Triglyceride and oxLDL levels were only significantly associated with the diagnosis of CS. CONCLUSION: Hypercortisolism is related to the increase observed in triglycerides and oxLDL levels, and, in combination with insulin resistance, acts to increase waist circumference and amplify the inflammatory process, key factors for the development of cardiovascular disease.

Chronic exposure to TiO2 micro- and nano particles: A biochemical and histopathological experimental study.

The aim of this work was to analyze the effects of long-term exposure to titanium dioxide (TiO2) micro- (MPs) and nanoparticles (NPs) (six and 12 months) on the biochemical and histopathological response of target organs using a murine model. Male Wistar rats were intraperitoneally injected with a suspension of TiO2 NPs (5 nm; TiO2-NP5 group) or MPs (45 µm; TiO2-NP5 group); the control group was injected with saline solution. Six and 12 months post-injection, titanium (Ti) concentration in plasma and target organs was determined spectrometrically (ICP-MS). Blood smears and organ tissue samples were evaluated by light microscopy. Liver and kidney function was evaluated using serum biochemical parameters. Oxidative metabolism was assessed 6 months post-injection (determination of superoxide anion by nitroblue tetrazolium (NBT) test, superoxide dismutase (SOD) and catalase (CAT), lipid peroxidation, and paraoxonase 1). Titanium (Ti) concentration in target organs and plasma was significantly higher in the TiO2-exposed groups than in the control group. Histological evaluation showed the presence of titanium-based particles in the target organs, which displayed no structural alterations, and in blood monocytes. Oxidative metabolism analysis showed that TiO2 NPs were more reactive over time than MPs (p < .05) and mobilization of antioxidant enzymes and membrane damage varied among the studied organs. Clearance of TiO2 micro and nanoparticles differed among the target organs, and lung clearance was more rapid than clearance from the lungs and kidneys (p < .05). Conversely, Ti concentration in plasma increased with time (p < .05). In conclusion, neither serum biochemical parameters nor oxidative metabolism markers appear to be useful as biomarkers of tissue damage in response to TiO2 micro- and nanoparticle deposits at chronic time points.

Air pollution induces morpho-functional, biochemical and biomechanical vascular dysfunction in undernourished rats.

Air pollution (gases and particulate matter -PM) and child undernutrition are globally recognized stressors with significant consequences. PM and its components breach the respiratory alveolar-capillary barrier, entering the vasculature transporting not only harmful particles and its mediators but, altering vascular paracrine and autocrine functions. The aim of this study was to investigate the effects of Residual Oil Fly Ash (ROFA), on the vasculature of young animals with nutritional growth retardation (NGR). Weanling rats were fed a diet restricted 20% (NGR) compared to ad libitum intake (control-C) for 4 weeks. Rats were intranasally instilled with 1 mg/kg BW of ROFA. After 24h exposure, histological and immunohistochemical, biochemical and contractile response to NA/ACh were evaluated in aortas. ROFA induced changes in the tunica media of the aorta in all groups regarding thickness, muscular cells and expression of Connexin-43. ROFA increased TGF-ß1 and decreased eNOs levels and calcium channels in C and NGR animals. An increment in cytokines IL-6 and IL-10 was observed in C, with no changes in NGR. ROFA exposure altered the vascular contractile capacity. In conclusion, ROFA exposure could increase the risk for CVD through the alteration of vascular biochemical parameters, a possible step of the endothelial dysfunction.

Systemic effect of TiO2 micro- and nanoparticles after acute exposure in a murine model.

The surface of a biomedical implant can be a potential endogenous source of release of microparticles (MPs) and nanoparticles (NPs) into the biological environment. In addition, titanium particles from exogenous sources can enter the body through inhalation, ingestion, or dermal contact. The aim of this work was to evaluate the biological response of the lung, liver, and kidneys to acute exposure to titanium dioxide (TiO2 ). Male Wistar rats were intraperitoneally injected with a suspension of 45 µm or 5 nm TiO2 particles. One month post-exposure, titanium concentration was determined spectrometrically (ICP-MS) in plasma and target organs. Blood smears and organ tissue samples were examined histopathologically, and oxidative metabolism was analyzed (superoxide anion by nitro blue tetrazolium (NBT) test; superoxide dismutase (SOD) and catalase (CAT); lipid peroxidation; paraoxonase 1). Liver (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) and kidney (urea, creatinine) function was evaluated using serum biochemical markers. Microchemical and histological analysis revealed the presence of particles, though no structural alterations, in TiO2 -exposed groups. NBT test showed an increase in the percentage of reactive cells and antioxidant enzyme consumption in lung samples in the 45 µm and 5 nm TiO2 -exposed groups. Only the 5 nm particles caused a decrease in SOD and CAT activity in the liver. No changes in renal oxidative metabolism were observed in either of the TiO2 -exposed groups. Determination of serum biochemical markers and analysis of oxidative metabolism are not early bioindicators of tissue damage caused by TiO2 MPs and NPs.

Association of common variants in JAK2 gene with reduced risk of metabolic syndrome and related disorders.

BACKGROUND: Disturbances in leptin and insulin signaling pathways are related to obesity and metabolic syndrome (MS) with increased risk of diabetes and cardiovascular disease. Janus kinase 2 (JAK2) is a tyrosine kinase involved in the activation of mechanisms that mediate leptin and insulin actions. We conducted a population cross-sectional study to explore the association between two common variants in JAK2 gene and MS related traits in 724 Argentinean healthy male subjects. METHODS: A total of 724 unrelated men aged 37.11 ± 10.91 yr were included in a cross-sectional study. Physical examination, anthropometric measurements and biochemical analysis were determined by a standardized protocol. rs7849191 and rs3780378 were genotyped. Analyses were done separately for each SNP and followed up by haplotype analysis. RESULTS: rs7849191 and rs3780378 were both associated with reduced risk of MS [p = 0.005; OR (95%CI) = 0.52 (0.33-0.80) and p = 0.006; OR (95% CI) = 0.59 (0.40-0.86) respectively, assuming a dominant model]. rs3780378 T allele was associated with triglyceridemia values under 150 mg/dl [p = 0.007; OR (95%CI) = 0.610 (0.429-0.868)] and TT carriers showed lower triglycerides (p = 0.017), triglycerides/HDL-C ratio (p = 0.022) and lipid accumulation product (p = 0.007) compared to allele C carriers. The two-SNPs-haplotype analysis was consistent with single locus analysis. CONCLUSIONS: It was found for the first time, significant associations of JAK2 common variants and related haplotypes with reduced risk of MS. These findings could be explained by the role of JAK2 in insulin and/or leptin signaling.

High risk of cardiovascular disease in iron overload patients.

INTRODUCTION: Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage. Whether increased iron stores are involved in the pathogenesis of cardiovascular disease remains controversial. OBJECTIVES: To study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO. METHODS: Twenty male patients with IO were compared with 20 sex- and age-matched controls. General biochemical parameters, lipoprotein profile, and activities of paraoxonase 1, employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) and CETP were determined. RESULTS: IO patients showed higher levels of HOMA-IR and triglycerides [median (Q1-Q3)] [128 (93-193) vs. 79(51-91) mg dL(-1) , P < 0·0005] while lower high-density lipoprotein (HDL) cholesterol (mean ± SD) (41 ± 9 vs. 52 ± 10 mg dL(-1) , P < 0·0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol [3·2 (2·0-5·1) vs. 1·5 (1·0-1·9), P < 0·0005] ratio and oxidized low-density lipoprotein levels [94 (64-103) vs. 68 (59-70) IU L(-1) , P < 0·05] were increased in the patient group. Although no difference was observed in ARE activity, PON activity was decreased in IO patients [246 (127-410) vs. 428 (263-516) nmol mL(-1) min(-1) , P < 0·05]. In addition, CETP and Lp-PLA(2) activities were also increased in the patients (189 ± 31 vs. 155 ± 36% ml(-1) h(-1) , P < 0·005; and 10·1 ± 2·9 vs. 8·2 ± 2·4 µmol mL(-1) h(-1) , P < 0·05, respectively). Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B = 65·9, P < 0·0001, r(2) = 0·35), as well as ferritin concentration of Lp-PLA(2) activity (B = 3·7, P < 0·0001, r(2) = 0·40) after adjusting for confounding variables. CONCLUSIONS: IO patients presented not only insulin resistance but also metabolic alterations that were related to elevated iron stores and are associated with high risk of cardiovascular disease.

[Increased iron store and its relationship with cardiovascular disease]. / Aumento de los depósitos de hierro y su relación con la enfermedad cardiovascular.

In the last years, great advance has been achieved in the control of several of the classic atherogenic risk factors; nonetheless, the incidence of cardiovascular disease (CVD) still remains high. Among the disorders which are associated with CVD, increased iron stores have been described as one of them. Its study gained relevance since the "iron hypothesis", which postulates that low iron levels exert a protective effect on cardiovascular system, was elaborated. In spite of the numerous studies carried out to test this hypothesis, the results have been controversial. On the other hand, much knowledge regarding iron metabolism has been gained since the description of the regulatory hormone, hepcidin. The studies on hepcidin physiologic functions allowed the elaboration of new hypothesis that could explain the results formerly conceived as inconsistent. The aim of the present review is to describe, in light of the newest advances in iron metabolism regulation and its association with inflammation, the current state of knowledge regarding the possible role of iron overload as a risk factor of CVD.

Increased Cholesteryl Ester Transfer Protein and Lipoprotein-Associated Phospholipase A2 Activities in Children and Adolescents Presenting High Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio.

OBJECTIVE: To explore the association between Triglyceride/High-density lipoprotein cholesterol (TG/HDL-C) index and these enzymes and proteins in a pediatric population. METHODS: Children and adolescents (7-14 y old) were recruited (n = 150) and anthropometric data were registered. Glucose, TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C plus cholesteryl ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) activities were determined. RESULTS: Twenty-five individuals presented TG/HDL-C ratio ≥ 3.0. These individuals exhibited higher TG [164 (126-186) vs. 65 (48-72) mg/dL; p < 0.01] CETP [250 (232-263) vs. 223 (193-237)% mL/min; p < 0.01] and Lp-PLA2 (4.5 ± 1.9 vs. 3.5 ± 1.3; p < 0.05) plus lower HDL-C [41 (37-49) vs. 52 (48-62) mg/dL; p < 0.01] compared to an age-matched group with TG/HDL-C < 3.0. TG/HDL-C ratio was associated to CETP (p < 0.01) and Lp-PLA2 (p < 0.05). Multiple lineal regression analyses showed TG/HDL-C index as an independent predictor of CETP (r2 = 0.29; beta = 0.49; p < 0.01) and Lp-PLA2 (r2 = 0.21; beta = 0.32; p < 0.05) activities. CONCLUSION: Children and adolescents with TG/HDL-C ≥ 3.0 presented a more atherogenic lipid profile and higher CETP and Lp-PLA2 activities, which would indicate alterations in lipoprotein metabolism and quality.

Effect of Tocilizumab on LDL and HDL Characteristics in Patients with Rheumatoid Arthritis. An Observational Study.

BACKGROUND: In patients with rheumatoid arthritis (RA), qualitative alterations of low and high-density lipoproteins (LDL and HDL, respectively) might partially explain their increased cardiovascular risk. Tocilizumab has been associated with an increase in lipids, including triglyceride (TG) and cholesterol levels. The aim of this study is to evaluate the effect of tocilizumab on certain LDL and HDL characteristics (oxidized LDL levels, HDL-associated enzymes, chemical composition of both total HDL and HDL3c subpopulation, and their capacity to promote cellular cholesterol efflux) at baseline and 3 months after the start of treatment in patients with RA. METHODS: Twenty-eight RA patients (ACR/EULAR 2010 criteria) with indication of treatment with tocilizumab were included in the present study. Clinical assessment [Health assessment questionnaire (HAQ)], disease activity score 28 (DAS28), high-sensitivity C reactive protein (hsCRP) concentration, lipid profile, and lipoprotein (a) [Lp(a)] levels were evaluated in all patients at baseline and after 3 months of treatment with tocilizumab. Lipoprotein characteristics were evaluated through the levels of oxidized LDL (OxLDL), the activity of paraoxonase (PON) 1, the composition of total HDL and small, dense HDL3c subpopulation, and their ability to promote cellular cholesterol efflux. RESULTS: After 3 months of treatment with tocilizumab, HAQ (- 23%, p < 0.05), DAS28 (- 49%, p < 0.001), and hsCRP (- 94%, p < 0.01) levels decreased significantly. Total cholesterol (TC), LDL-C, non-HDL-C, and apo B levels showed a significant increase after treatment (TC: + 7.0%, p < 0.01; LDL-C: + 10%, p < 0.01; non-HDL-C: + 9.9%, p < 0.01; and apo B: + 9.6%, p < 0.05). Decreases in Lp(a) and OxLDL levels were also observed after treatment [Lp(a): - 50%, p < 0.01; and oxLDL: - 5.4%, p < 0.05]. The latter was in accordance with the increment detected in PON activity. No changes were observed in HDL capacity to promote cholesterol efflux (p > 0.05) in the whole group. CONCLUSIONS: Treatment with tocilizumab reduced hsCRP levels and displayed positive effects on certain lipoprotein-related parameters, such as a potent decrease inLp(a) and a reduction in OxLDL levels. Moreover, HDL capacity to promote cellular cholesterol efflux was maintained after 3 months of treatment.

Effect of Roux-en-Y Gastric Bypass on Lipoprotein Metabolism and Markers of HDL Functionality in Morbid Obese Patients.

PURPOSE: Morbid obesity represents the most severe form of obesity and surgical intervention would be its only successful treatment. Bariatric surgery could generate modifications in carbohydrate metabolism and in lipid profile plus lipoprotein-associated proteins and enzymes, such as lipoprotein-associated phoslipase A2 (Lp-PLA2), cholesteryl ester transfer protein (CETP), and paraoxonase (PON) 1. The aim of the present study was to analyze changes in inflammation markers, carbohydrate metabolism, and lipid parameters in patients who underwent bariatric surgery. METHODS: Thirty-seven patients with morbid obesity were recruited. Evaluations were performed before (T0) and 1 (T1) and 6 (T2) months after surgery. Glucose, insulin, high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, apolipoproteins (apo) A-I, and B plus Interleukin 1ß and 6 levels in addition to CETP, Lp-PLA2, and PON 1 activities were determined. RESULTS: Body mass index decreased at T1 and T2 (p < 0.01). An improvement in all markers of insulin resistance (p < 0.05) was observed at T1. hsCRP levels diminished at T2 (p < 0.05). Triglyceride levels decreased at T1 and T2 (p < 0.05). HDL-C and apo A-I showed a decrease at T1 which was completely reversed at T2 (p < 0.05). Lp-PLA2 activity increased at T1, which was reversed at T2 (p < 0.05), and CETP activity was diminished at T2 (p < 0.05). PON and ARE activities decreased at T1 and partially recovered at T2 (p < 0.05). CONCLUSIONS: These results would be indicative of a favorable effect of bariatric surgery on markers of carbohydrate metabolism and cardiovascular disease lipid risk factors.

Phospholipid transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis is directly correlated with HDL-cholesterol levels and is not associated with cardiovascular risk.

BACKGROUND AND AIMS: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. METHODS AND RESULTS: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. CONCLUSIONS: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.

[Atherogenic lipoprotein remnants in humans]. / Lipoproteínas remanentes aterogénicas en humanos.

Remnant lipoproteins (RLPs) are the lipolytic product of triglycerides transported by very low density lipoproteins (VLDL) of hepatic and intestinal origin and intestinal chylomicrons. Lipoprotein lipase activity hydrolyse triglycerides in several steps, producing heterogeneous particles. Fasting plasma concentration in normolipidemic subjects is low, but it increases in post-prandial states. Genetic alterations in Apo-E subtypes increases RLPs plasma concentration and produce dyslipoproteinemia phenotype. RLPs atherogenicity depends on their role as endothelial injuring factors, their impaired recognition by lipoprotein receptors, and their susceptibility to oxidative stress. They also promote the circulation of molecular adhesion molecules, the internalization in subendothelial macrophages via scavenger receptors and the accumulation in foam cells, all of them early mechanisms of atheromatosis. RLPs metabolism has been a subject of controversial studies. Their origin from different lipoproteins may explain their structural heterogeneity, therefore increasing the methodological difficulties to include RLPs in the atherogenic lipoprotein profile in the epidemiological studies of the field. Last advances on metabolism of RLPs and their emergent clinical role justifies an up dated revision of RLPs.