¿Ser taxista es un factor de riesgo cardiovascular? Análisis del perfil lipídico e IMC / Is being a taxi driver a cardiovascular risk factor? Analysis of the lipid profile and BMI

Contexto: existen múltiples factores de riesgo modificables involucrados en la aparición de eventos cardiovasculares, como los niveles de lipoproteína de baja densidad elevados, lipoproteína de alta densidad disminuida, la hipertensión arterial, el hábito tabáquico, consumo de alcohol y el sedentarismo. Objetivo: es relacionar el índice de masa corporal con el perfil lipídico en los conductores de taxi, además conocer los hábitos y prácticas de vida relacionados. Sujetos y métodos: estudio observacional, transversal, epidemiológico en el que se evaluó 112 participantes, 89 (70,46%) hombres y 23 (20.53%) mujeres, con una edad entre 19 y 68 años de edad; se midió peso, talla, IMC, presión arterial y se determinó el perfil lipídico. Resultados: 32 individuos tienen peso normal, mientras que 60 tienen obesidad, 19 obesidad tipo 1 y 1 obesidad tipo 2. Conclusión: los conductores de taxi tienen alta prevalencia de obesidad. Los resultados de este estudio servirán de base para el diseño de intervenciones educativas centradas en la motivación y el autocuidado para prevenir el sobrepeso y predecir el riesgo de padecer un evento cardiovascular. (AU)

Context: there are multiple modifiable risk factors involved in the onset of cardiovascular events, such as high levels of low density lipoprotein, decreased high density lipoprotein, high blood pressure, smoking, alcohol consumption and sedentary lifestyle. Objective: to relate the body mass index with the lipid profile in taxi drivers, in addition to knowing the habits and related life practices. Subjects and methods: observational, cross-sectional, epidemiological study in which 112 participants were evaluated, 89 (70.46%) men and 23 (20.53%) women, with an age between 19 and 68 years of age; weight, height, BMI, blood pressure were measured and the lipid profile was determined. Results: 32 individuals have normal weight, while 60 have obesity, 19 obesity type 1 and 1 obesity type 2. Conclusion: taxi drivers have a high prevalence of obesity. The results of this study will serve as a basis for the design of educational interventions focused on motivation and self-care to prevent overweight and predict the risk of suffering a cardiovascular event. (AU)

Identificación de variantes en el gen LMF1 asociadas con hipertrigliceridemia primaria / Identification of variants in LMF1 gene associated with primary hypertriglyceridemia

La mayoría de las hipertrigliceridemias (HTG) primarias graves se diagnostican en la edad adulta, y sus bases moleculares no se han dilucidado completamente. Varios son los genes relacionados con este tipo de HTG, entre ellos el gen LMF1, que codifica la proteína Lmf1, la cual participa en la función de la lipoproteína lipasa (LpL). Teniendo en cuenta estos hechos, nuestro objetivo es identificar las variantes génicas comunes y no comunes en el gen LMF1en sujetos con HTG primaria. Hemos secuenciado el promotor, los exones y las regiones exón-intrón del gen LMF1 en 112 pacientes con HTG primaria grave, definida por triglicéridos por encima de 500 mg/dl, excluyendo causas secundarias. Cinco pacientes (4,46%) fueron portadores de 4 variantes raras en LMF1asociadas previamente a HTG. Además, se identificaron 2 variantes comunes con una frecuencia alélica diferente de la que se observa en población general: c.194-28 T>G y c.729+18C>G.Se llevó a cabo un análisis bioinformático de las variantes encontradas, identificando las variantes p.Arg364Gln, p.Arg451Trp, p.Pro562Arg y p.Leu85Leu como potencialmente dañinas. Nuestros resultados sugieren que el gen LMF1 contribuye a la etiología de la HTG primaria grave en un porcentaje significativo de los pacientes, con una combinación de mutaciones de efecto entre moderado y agresivo y polimorfismos clásicamente asociados con esta dislipidemia

The majority of severe primary hypertriglyceridemia (HTG) are diagnosed in adults, and their molecular bases have not yet been fully defined. The promoter, coding regions and intron-exon boundaries of LMF1 were sequenced in 112 patients with severe primary hipertrigliceridemia (defined as TG above 500 mg/dl). Five patients (4.46%) were carriers of four rare variants in the LMF1 gene associated with HTG, which participate in lipoprotein lipase (LpL) function. Also, we have identified two common variants, c.194-28 T>G and c.729+18C>G that were associated with HTG, with a different allelic frequency to that observed in the general population. A bioinformatic analysis of all found variants was conducted, defining the following as potentially harmful: p.Arg364Gln, p.Arg451Trp, p.Pro562Arg and p.Leu85Leu.Our results suggest that LMF1 mutations are involved in a substantial proportion of cases with severe HTG, putting together the moderate-aggressive effect of rare mutations with polymorphisms classically associated with this disease

Hipertrigliceridemia y LMF 1: otra pieza del rompecabezas / Hypertriglyceridemia and LMF 1: Another piece of the puzzle

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A novel apolipoprotein C-II mimetic peptide that activates lipoprotein lipase and decreases serum triglycerides in apolipoprotein E-knockout mice.

Apolipoprotein A-I (apoA-I) mimetic peptides are currently being developed as possible new agents for the treatment of cardiovascular disease based on their ability to promote cholesterol efflux and their other beneficial antiatherogenic properties. Many of these peptides, however, have been reported to cause transient hypertriglyceridemia due to inhibition of lipolysis by lipoprotein lipase (LPL). We describe a novel bihelical amphipathic peptide (C-II-a) that contains an amphipathic helix (18A) for binding to lipoproteins and stimulating cholesterol efflux as well as a motif based on the last helix of apolipoprotein C-II (apoC-II) that activates lipolysis by LPL. The C-II-a peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells similar to apoA-I mimetic peptides. Furthermore, it was shown in vitro to be comparable to the full-length apoC-II protein in activating lipolysis by LPL. When added to serum from a patient with apoC-II deficiency, it restored normal levels of LPL-induced lipolysis and also enhanced lipolysis in serum from patients with type IV and V hypertriglyceridemia. Intravenous injection of C-II-a (30 mg/kg) in apolipoprotein E-knockout mice resulted in a significant reduction of plasma cholesterol and triglycerides of 38 ± 6% and 85 ± 7%, respectively, at 4 hours. When coinjected with the 5A peptide (60 mg/kg), the C-II-a (30 mg/kg) peptide was found to completely block the hypertriglyceridemic effect of the 5A peptide in C57Bl/6 mice. In summary, C-II-a is a novel peptide based on apoC-II, which promotes cholesterol efflux and lipolysis and may therefore be useful for the treatment of apoC-II deficiency and other forms of hypertriglyceridemia.

NO-1886 ameliorates glycogen metabolism in insulin-resistant HepG2 cells by GSK-3ß signalling.

OBJECTIVES: The aim of the study was to elucidate the possible role and mechanism of NO-1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. METHODS: HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. KEY FINDINGS: We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin-induced glucose consumption (from 2.89 ± 0.85 mm in the control to 0.57 ± 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO-1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin-resistant HepG2 cells. Maximum stimulation effects were observed with 10 µm NO-1886 for 24 h. Compared with the dimethyl sulfoxide-treated group, 2.5 µm NO-1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO-1886 increased the protein content of P-GSK-3ßser(9) and decreased the protein level of GSK-3ß in insulin-resistant HepG2 cells, but NO-1886 didn't change the protein levels of PI3-Kp85 and Akt2. CONCLUSION: Lipoprotein lipase activator NO-1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK-3 signalling.

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells.

AIM: To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. METHODS: Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. RESULTS: Ibrolipim 5 and 50 µmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. CONCLUSION: Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway.

Characterization of a novel murine preadipocyte line, AP-18, isolated from subcutaneous tissue: analysis of adipocyte-related gene expressions.

Adipocyte lines are a useful tool for adipocyte research. Recently, a new preadipocyte line designated AP-18 was established from subcutaneous tissue of the C3H/He mouse. In this study, we further characterized AP-18 cells. Adipocyte differentiation was assessed by accumulation of fat droplets stained by Oil Red O. The expression of the preadipocyte- or adipocyte-specific genes and adipocytokine genes was analysed qualitatively by RT-PCR and quantitatively by real-time PCR in comparison with the LM cell, a murine fibroblast line, and the 3T3-L1 cell, respectively. AP-18 cells were fibroblastoid in maintenance culture. After the confluence, fat droplets were accumulated in 50-60% of the cells cultured in the medium alone and in 70-90% of the cells cultured with insulin within 2 to 3 weeks. The fat accumulation was not promoted by the addition of dexamethazone, IBMX (3-isobutyl-1-methylxanthine) or troglitazone in combination with insulin, which were obligatory for differentiation of the 3T3-L1 cell, a murine preadipocyte line. Throughout the differentiation, AP-18 cells expressed Pref-1, LPL, C/EBP beta, C/EBP delta, RXR alpha, C/EBP alpha, PPAR gamma, RXR gamma, aP2, GLUT4, SCD1, UCP2, UCP3, TNFalpha, resistin, leptin, adiponectin and PAI-1 genes, but not the UCP1 gene, indicating that the cell is derived from WAT (white adipose tissue). The time course of these gene expressions was similar to that of 3T3-L1 cells, although the expressions were slower and lower in AP-18 cells. These data indicate that AP-18 cells are preadipocytes originated from WAT and differentiate into adipocytes under more physiological conditions than 3T3-L1 cells. AP-18 may be useful in adipocyte research.

NO-1886, a lipoprotein lipase activator, attenuates contraction of rat intestinal ring preparations.

Various intestinal symptoms or diseases are closely associated with intestinal motility, which may be altered by metabolic disturbances associated with diabetes and obesity. It is therefore important that drugs used in the treatment of metabolic disorders should not have any adverse effects on the intestine. In the present study, we examined whether [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886), a lipoprotein lipase activator with anti-diabetic and/or anti-obese activity, affects stimulant-induced intestinal contractility. Administration of NO-1886 to intestinal ring preparations of ileum, rectum and colon isolated from Wistar rats attenuated or relaxed contraction induced by a high K+ environment or acetylcholine (ACh). This effect of NO-1886 was dependent on extracellular Ca(2+) and intracellular myosin light chain kinase activity. Our results also showed that ACh-induced colonic contraction was significantly higher in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) than in the non-obese Long-Evans Tokushima Otsuka (LETO) rats. The hypercontractility observed in the colons of OLETF rats occurred concomitantly with an elevation in muscarinic M3 ACh receptor protein levels. Administration of NO-1886 attenuated the obesity-induced hypercontractility of the colonic rings of OLETF rats. Thus, intestinal contractile system would be a novel pharmacological target of the lipoprotein lipase activator NO-1886.

Five-week, low-glycemic index diet decreases total fat mass and improves plasma lipid profile in moderately overweight nondiabetic men.

OBJECTIVE: To evaluate whether a 5-week low-glycemic index (LGI) diet versus a high-glycemic index (HGI) diet can modify glucose and lipid metabolism as well as total fat mass in nondiabetic men. RESEARCH DESIGN AND METHODS: In this study, 11 healthy men were randomly allocated to 5 weeks of an LGI or HGI diet separated by a 5-week washout interval in a crossover design. RESULTS: The LGI diet resulted in lower postprandial plasma glucose and insulin profiles and areas under the curve (AUCs) than the HGI diet. A 5-week period of the LGI diet lowered plasma triacylglycerol excursion after lunch (AUC, P < 0.05 LGI vs. HGI). These modifications were associated with a decrease in the total fat mass by approximately 700 g (P < 0.05) and a tendency to increase lean body mass (P < 0.07) without any change in body weight. This decrease in fat mass was accompanied by a decrease in leptin, lipoprotein lipase, and hormone-sensitive lipase RNAm quantities in the subcutaneous abdominal adipose tissue (P < 0.05). CONCLUSIONS: We concluded that 5 weeks of an LGI diet ameliorates some plasma lipid parameters, decreases total fat mass, and tends to increase lean body mass without changing body weight. These changes were accompanied by a decrease in the expression of some genes implicated in lipid metabolism. Such a diet could be of benefit to healthy, slightly overweight subjects and might play a role in the prevention of metabolic diseases and their cardiovascular complications.

Isolation of two distinct activator proteins for lipoprotein lipase from ovine plasma.

Two distinct activator proteins for lipoprotein lipase (LPL) have been isolated in approximately equal amounts from ovine plasma. These low molecular weight proteins were readily separated from each other on the basis of size and charge. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated proteins of Mr about 8000 and 5000, with pI in urea-containing gels of about 5.1 and 4.8 respectively. Each of the ovine activator proteins was as effective as human apolipoprotein C-II (apo C-II) in activating LPL, with 1 microgram/ml giving near to maximum activation, and in lowering the apparent Km of LPL for triolein substrate. As the ratio of activator to triolein increased from 0.16 to 5.2 (micrograms/mg) the apparent Km fell from about 0.5 to 0.18 mM. Whereas human apo C-II and the two ovine activators were equally effective in stimulating the hydrolysis of triolein, differences were observed between the human and ovine activators when p-nitrophenylbutyrate was used as substrate. Unlike human apo C-II, which produced significant inhibition of p-nitrophenylbutyrate hydrolysis, the ovine activators were without effect. This suggests that the interaction between the ovine activators and LPL is different from that of human apo C-II.

The effects of oral agent or insulin treatments on the plasma lipoproteins and the plasma lipoprotein lipase activator in diabetic patients.

The structure and the metabolism of plasma lipoproteins are altered in diabetes mellitus. Insulin or oral agent treatments affect the lipoprotein metabolism in addition to improving hyperglycemia. However, it is not clear whether the alterations seen in lipoproteins during treatment are related to the degree of diabetic control or to the mode of diabetic treatment. The effects of insulin or oral agent treatments on the plasma lipoproteins and lipoprotein lipase activator were compared in a strictly defined non-obese, non-insulin dependent diabetic patient. Both treatment groups had similar plasma triglyceride, total cholesterol, low and high density lipoprotein cholesterol, and lipoprotein lipase activator levels. Lipoprotein lipase activator contents of the very low density lipoproteins correlated positively with their triglyceride (r = 0.803 in insulin, r = 0.828 in oral agent treated patients) and protein (r = 0.713 in insulin, r = 0.862 in oral agent treated patients) contents. The findings of this study indicated that plasma lipid levels, very low density lipoprotein compositions, and lipoprotein lipase activator contents were not significantly different in non-obese, non-insulin dependent diabetic patients treated with either oral hypoglycemic agents or insulin.

Hydrolysis of plasma triacylglycerol-rich lipoproteins from immature and laying hens (Gallus domesticus) by lipoprotein lipase in vitro.

Very-low-density (VLD) lipoproteins and portomicrons were isolated from the plasma of immature and laying hens and their size, lipid composition and susceptibility to hydrolysis by lipoprotein lipase were compared. In agreement with other studies, VLD lipoproteins from laying hens were found to be smaller and have a different lipid composition than VLD lipoproteins from immature hens. Portomicrons from immature and laying hens had mean diameters of about 150 nm and similar lipid compositions. Hydrolysis of VLD lipoproteins from immature hens, and portomicrons from immature and laying hens, proceeded rapidly until at least 40% of the substrate had been used. In contrast only 1--15% of laying-hen VLD-lipoprotein triacylglycerol was readily hydrolysis occurred slowly. The limited susceptibility of laying-hen VLD lipoproteins appeared to be due to their low content of lipoprotein lipase activator apoprotein, which occurred despite an abundance of activator in the high-density lipoproteins of laying-hen plasma. The results provide further evidence that the liver of the laying hen synthesizes specialized lipoproteins. Their limited susceptibility to hydrolysis by lipoprotein lipase is probably a major factor in ensuring transport of lipid to yolk rather than to other tissues. The form of transport of dietary lipid, however, is similar in immature and laying hens.

Plasma lipids and lipoprotein lipase activating property in women on three different combinations of estrogens and progestins.

PIP: 71 healthy women aged 20-35, nonobese and who had received 1 of 3 different combinations of ethinyl estradiol and D-norgestrel for more than 6 months were studied to observe the influence of the drugs on the plasma lipids and lipoprotein lipase. The 3 combinations were: 1) 30 mcg ethinyl estradiol and 250 mcg D-norgestrel; 2) 50 mcg ethinyl estradiol and 250 mcg D-norgestrel; and 3) 50 mcg ethinyl estradiol and 500 mcg D-norgestrel. Results were compared to data from a similar study on 24 normal females who were not on OC. Patients in groups 1 and 2 had significantly elevated total plasma cholesterol and LDL-C (high density lipoprotein cholesterol) as compared to the controls. In group 2 total plasma LPL (lipoprotein lipase) activator property was significantly lower than in controls, but total plasma triglycerides level was significantly higher. Patients in group 3 has significantly lower total plasma triglycerides but high LPL activating property than women in group 2. These results show that OC may affect plasma triglycerides through the influence of apolipoproteins that modulate lipoprotein lipase activity.^ieng