Stratification in Heterozygous Familial Hypercholesterolemia: Imaging, Biomarkers, and Genetic Testing.

PURPOSE OF REVIEW: Heterozygous familial hypercholesterolemia (HeFH) is the most common monogenic autosomal dominant disorder. However, the condition is often underdiagnosed and undertreated. The objective of this review is to provide an update on the risk stratification in patients with HeFH, incorporating new cardiovascular imaging techniques, various biomarkers, and genetic studies. RECENT FINDINGS: The diagnosis of HeFH places patients in a high cardiovascular risk category due to the increased incidence of premature atherosclerotic cardiovascular disease. However, the level of risk varies significantly among different individuals with HeFH. Achieving an optimal stratification of cardiovascular risk is crucial for establishing appropriate and accurate treatment and management strategies. Different new tools such as risk scores have emerged in recent years, aiding physicians in assessing the risk stratification for HeFH using imaging, biomarkers, and genetics. This review emphasizes that not all patients with HeFH face the same cardiovascular risk. By utilizing different assessment tools, we can identify those who require more intensive monitoring, follow-up, and treatment.

Zinc deficiency and a high-fat diet during growth: Metabolic and adipocyte alterations in rats.

BACKGROUND AND AIMS: To evaluate the effects of a high-fat diet during post-weaning growth on intermediate metabolism and retroperitoneal adipose tissue, in adult male rats exposed to adequate or deficient zinc intake during prenatal and postnatal life. METHODS AND RESULTS: Female Wistar rats were fed low- or control-zinc diets from pregnancy to offspring weaning. Male offspring born from control mothers were fed either control or high-fat, control-zinc diets for 60 days. Male offspring born from zinc deficient mothers were fed either low-zinc or high-fat, low-zinc diets for 60 days. At 74 days of life, oral glucose tolerance test was performed. In 81-day-old offspring, blood pressure, lipid profile, plasmatic lipid peroxidation and serum adiponectin level were determined. In retroperitoneal adipose tissue, we evaluated oxidative stress, morphology and adipocytokines mRNA expression. Low-zinc diet induced adipocytes hypertrophy, increased oxidative stress, and decreased adiponectin mRNA expression in adipose tissue. Low-zinc diet increased systolic blood pressure, triglyceridemia, plasmatic lipid peroxidation and glycemia at 3 h after glucose overload. Animals fed high-fat or high-fat, low-zinc diets showed adipocytes hypertrophy, decreased adiponectin mRNA expression, and increased leptin mRNA expression and oxidative stress in adipose tissue. They also exhibited decreased serum adiponectin levels, increased triglyceridemia, plasmatic lipid peroxidation and area under the oral glucose tolerance curve. High-fat, low-zinc diet induced greater alterations in adipocyte hypertrophy, leptin mRNA expression and glucose tolerance test than high-fat diet. CONCLUSION: Zinc deficiency since early stages of intrauterine life could increase susceptibility to metabolic alterations induced by high-fat diets during postnatal life.

Uncharted risk measures for the management of sustainable mining.

Governments commit to ensuring the welfare of their citizens by drafting and enforcing regulations that ultimately ensure the sustainability of mining. This study contributes to improving the sustainability of mining throughout the mine's lifecycle until the final destination of the mining products. We propose recommendations that address the sustainability of mining from a global perspective, framed around the United Nations Sustainable Development Goals (SDGs), following waste hierarchy with Common Agricultural Policies, and policies from the Green Deal on climate, energy, transport, and taxation. Tailings are the most significant source of environmental impact in mining operations and, therefore, must comply with controlling regulations through Tailings Management Facilities (TMFs). However, there have been several mining accidents involving TMFs worldwide. The recommendations begin during planning, preconstruction, and construction with practices such as fair consultations, tax revenue fairness, and mandatory insurance. The operation and management support parallel industries to mining and supporting health and education. Emergency planning involves the surrounding communities in mock drills and environmental monitoring. In the closure and rehabilitation, remediation technologies such as phytoremediation, carbon sequestration incentives, and biomass valorization are recommended. Finally, supporting a circular economy by prioritizing ethical consumption, resource reduction, material recovery, and replacing toxic minerals and materials from the start with "benign by design" is recommended. The strategies involve stakeholders directly or indirectly related to the mining companies' contamination and demonstrate a commitment to the SDGs, offering a holistic perspective on scientific, social, and regulatory issues. Integr Environ Assess Manag 2023;19:949-960. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Remnant cholesterol levels are associated with severity and death in COVID-19 patients.

Coronavirus disease-19 (COVID-19) patients with severe complications present comorbidities like cardiovascular-disease, hypertension and type-2 diabetes mellitus (DM), sharing metabolic alterations like insulin resistance (IR) and dyslipidemia. Our objective was to evaluate the association among different components of the lipid-lipoprotein profile, such as remnant lipoprotein (RLP)-cholesterol, in patients with COVID-19, and to analyze their associations with the severity of the disease and death. We studied 193 patients (68 (29-96) years; 49.7% male) hospitalized for COVID-19 and 200 controls (46 (18-79) years; 52.5% male). Lipoprotein profile, glucose and procalcitonin were assessed. Patients presented higher glucose, TG, TG/HDL-cholesterol and RLP-cholesterol levels, but lower total, LDL, HDL and no-HDL-cholesterol levels (p < 0.001). When a binary logistic regression was performed, age, non-HDL-cholesterol, and RLP-cholesterol were associated with death (p = 0.005). As the COVID-19 condition worsened, according to procalcitonin tertiles, a decrease in all the cholesterol fractions (p < 0.03) was observed with no differences in TG, while levels of RLP-cholesterol and TG/HDL-cholesterol increased (p < 0.001). Lower levels of all the cholesterol fractions were related with the presence and severity of COVID-19, except for RLP-cholesterol levels and TG/HDL-cholesterol index. These alterations indicate a lipid metabolic disorder, characteristic of IR states in COVID-19 patients. RLP-cholesterol levels predicted severity and death in these patients.

Phenotype of definite familial hypercholesterolemia with negative genetic study in Argentina.

Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.

Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.

Phenotype of definite familial hypercholesterolemia with negative genetic study in Argentina / Fenotipo de hipercolesterolemia familiar definitivo con estudio genético negativo en Argentina

Abstract Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.

Resumen Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.

Fenotipo de hipercolesterolemia familiar definitivo con estudio genético negativo en Argentina.

Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.

Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.

Fish oil diet effects on alveolar bone loss, in hypercholesterolemic rats.

This study evaluated the effects of replacing a saturated fat diet by n-3 polyunsaturated fatty acids (n-3PUFA), on alveolar bone loss in hypercholesterolemic rats with experimental periodontitis (PD). METHODS: Eight week old Wistar rats were assigned according to dietary intake. Control group (C, n = 15) fed a commercial diet throughout the experiment. Atherogenic group (AT, n = 30) fed AT diet for 3 weeks; thereafter, AT was randomized to receive either a n-3PUFA (n = 15) or to continue with AT (n = 15) diet. Subsequently, PD was induced in all groups by unilateral ligature (L) of the first molar (M1) of the left mandible, non-ligated contralateral molars served as controls. After every week of PD induction, 5 rats per group were euthanized. Serum was collected for lipids assays and hemi-mandibles were subjected to histomorphometric (% upper and lower interradicular bone volume and periodontal ligament height, hPDL) and radiographic analyses (periodontal bone support, PBS, in ligated teeth, between M1-M2). RESULTS: Rats fed n-3PUFA diet rapidly induced a significant reduction in the serum lipids (p < 0.001). In all rats the ligated teeth showed a greater bone loss as compared with the unligated molars. At the end of the experiment the AT + L was the worst in % lower bone volume (p < 0.01), hPDL and PBS (p < 0.05). In contrast, rats fed n-3PUFA + L was similar to those rats fed C diet (p > 0.05). CONCLUSION: Alveolar bone and dyslipidemia improved by substituting saturated fat intake for a n-3PUFA rich diet, in hypercholesterolemic rats with PD.

Strategy for phytomanagement in an area affected by iron ore dam rupture: A study case in Minas Gerais State, Brazil.

In 2015, the Fundão tailing dam collapsed over the district of Bento Rodrigues (Mariana, Minas Gerais, Brazil) causing deaths, hundreds of homeless families and incalculable environmental degradation. Environmentally, economically and socially sustainable strategies are needed for the recovery of the affected areas. The main goal of this study was to evaluate the development, biomass production and toxic mineral elements absorption of three species of aromatic grasses (Chrysopogon zizanioides, Cymbopogon citratus and Cymbopogon winterianus). These three species were planted on polypropylene pots filled with the iron ore tailings collected from the topsoil of the Bento Rodrigues district. The pots were fertilized with increasing doses of organic compost associated with mycorrhizae as a phytomanagement strategy. A 4 × 2 factorial scheme was used. The seedlings were fertilized with four doses of organic compost, with or without mycorrhizae. At the highest dose of the organic compost (2 kg.plant-1), the total dry matter (dry matter of the aerial part + dry matter of the roots) for C. zizanioides was 4.5 times higher than the control (tailing only). For C. winterianus and C. Citratus was 3.8 and 2.8 times higher than the control, respectively. Inoculation with mycorrhizae improved biomass production, especially in C. zizanioides. The Fe and Mn levels found in the aerial part of the plants fertilized with organic compost were lower than those just growing on the iron ore tailings for the three species, which suggest that the organic matter apparently helped the plants in the exclusion of the hazardous substances and therefore increased the tolerance to these adverse environmental conditions. C. zizanioides, associated with organic matter and mycorrhizae, would be the recommended species. The proposed phytomanagement strategy can have a significant contribution to the gradual recovery of the affected area and also serve as a source of income for the local population.

Gestão dos resíduos sólidos orgânicos urbanos no Brasil: do ordenamento jurídico à realidade / Management of solid organic waste in Brazil: from legal ordinance to reality

RESUMO No Brasil, ainda se enterram, queimam ou lançam a céu aberto milhões de toneladas de resíduos orgânicos, em decorrência do desconhecimento de seu potencial de aproveitamento e dos impactos negativos que provocam quando dispostos inadequadamente. Este trabalho buscou analisar a inserção e a aplicação dos princípios e objetivos da Política Nacional de Resíduos Sólidos na gestão dos resíduos orgânicos e sua consonância com o Plano Nacional de Resíduos Sólidos e os Planos Plurianuais de Destinação Orçamentária da União. Lamentavelmente, os resíduos orgânicos foram pouco contemplados nas normativas, que não preveem programas ou ações específicas a serem implementados. A valoração dos resíduos orgânicos pode auxiliar na resolução de graves problemas ambientais, como degradação do solo, erosão e mudanças climáticas, além de desviar grande quantidade desses resíduos encaminhada a aterros sanitários e lixões no Brasil. Tanto as cidades quanto as empresas e a agricultura são amplamente beneficiadas ao considerar seus resíduos sólidos orgânicos como um "recurso" precioso, convertendo-o em adubo e/ou energia, gerando empregos e contribuindo para a redução dos custos de sua disposição. É preciso, portanto, além de melhorar a infraestrutura para a compostagem e a biometanização, investir intensivamente em programas de redução do desperdício de alimentos a fim de obter volumes menores para a reciclagem.

ABSTRACT In Brazil, millions of tons of solid organic wastes are still burnt or thrown into open dumps daily due to the lack of knowledge about their potential and the impacts they cause when improperly arranged. This paper aims to analyze the integration and application of the principles and objectives of the National Solid Waste Policy on the management of organic waste in the National Plan for Solid Waste and in the Multi-Year Plans of the Union Budget allocation. Unfortunately, it was observed that the law didn´t observe organic wastes, since it has no specific programs or planned actions. The valuation of organic wastes can help solve serious environmental problems, such as soil degradation, erosion, climate change, and divert large amounts of such waste sent to landfills and open dumps in Brazil. Cities, businesses and agriculture are greatly benefited by considering their organic "garbage" as a precious "resource", converting it into fertilizer and/or energy, generating jobs and reducing the cost of their disposal. Therefore, in addition to improving the infrastructure for composting and biomethanization, we must invest intensively in programs to reduce food waste, which will result in smaller volumes to be recycled.

Endothelial Lipase Is an Alternative Pathway for Fatty Acid Release from Lipoproteins: Evidence from a High Fat Diet Model of Obesity in Rats.

Lipoprotein lipase (LPL) and endothelial lipase (EL) are involved in lipoprotein metabolism. In insulin-resistance, their behavior is altered. Peroxisome proliferator-activated receptors (PPAR) and apoproteins (apo)CII and CIII could be partly responsible for these alterations. To evaluate this response, we assessed Lpl and Lipg expression, protein levels, and enzyme activity in adipose tissue (AT) and heart in an obesity model. Besides, we assessed the role of PPAR and apoC. Male Wistar rats were fed with standard diet (Control, n = 14) or high-fat diet (HFD, n = 14) for 14 weeks. Glucose and lipoprotein profiles were measured. Histological studies were performed in heart and epididymal AT. Lpl and Lipg were assessed by reverse transcription polymerase chain reaction (RT-qPCR), protein levels by Western Blot, and activities by radiometric assays. Cardiac and AT PPAR expression were measured by Western Blot and hepatic Apoc2 and Apoc3 mRNA by RT-qPCR. In HFD, fat deposits were observed in hearts, whereas AT presented a higher adipocyte size. In heart and AT, no differences were found in Lipg mRNA between groups, while AT Lpl mRNA and LPL protein were decreased in HFD, without differences in heart. In both tissues, EL protein levels and activity were increased and inversely associated with decreased LPL activity, being partially responsible for the atherogenic lipoprotein profile in HFD. PPARγ expression in AT was decreased in HFD, without differences in cardiac PPARδ expression and hepatic apoC mRNA. The increase in EL activity could be an alternative pathway for fatty acid release from lipoproteins and uptake in tissues with decreased LPL activity. In AT, PPARγ could be involved in enzyme regulation.

Nonalcoholic fatty liver disease associated with metabolic syndrome: Influence of liver fibrosis stages on characteristics of very low-density lipoproteins.

BACKGROUND: We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. METHODS: We studied 36 MetS patients with biopsy-proven NAFLD (MetS+NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS+NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0-F2, n=27) and severe (F3-F4, n=9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS+NAFLD type IV collagen 7S domain was measured. RESULTS: MetS+NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p<0.04). CETP activity tended to increase in MetS+NAFLD (p=0.058), while LPL activity was unchanged. Moreover, in MetS+NAFLD, adiponectin was decreased (p<0.001), and negatively correlated with VLDL-mass and VLDL particle number (p<0.05), independently of insulin-resistance. Within MetS+NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p<0.05), while type IV collagen was increased (p=0.009) and inversely correlated with large VLDL-% (p=0.045). CONCLUSIONS: In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function.

Adiponectina determinaría el predominio de VLDL alteradas en el síndrome metabólico / Adiponectin would determine the predominance of altered VLDL in metabolic syndrome / Adiponectina iria determinar o predomínio de VLDL alteradas na síndrome metabólica

El objetivo del trabajo fue evaluar si la reducción de adiponectina (ADP) en el síndrome metabólico (SMet), influencia las características aterogénicas de VLDL. Se estudiaron 45 pacientes con SMet y 15 controles sanos. En suero en ayunas se midió perfil lipídico, ácidos grasos libres (AGL), ADP, se aisló VLDL (d<1,006 g/L) caracterizándola en su composición química y tamaño (HPLC-exclusión molecular). En plasma post-heparínico se determinó la actividad de lipoproteína lipasa (LPL). En SMet VLDL mostró incremento de masa, número de partículas, contenido en triglicéridos-VLDL y mayor proporción de VLDL grandes (p<0,05). El incremento de AGL correlacionó con la masa de VLDL (r=0,36; p=0,009), número de partículas-VLDL (r=0,45; p=0,0006) y %-VLDL grandes (r=0,32; p=0,02). SMet mostró descenso en ADP (7,4±4,8 vs. 15,5±7,2 μg/mL, p=0,01) y en actividad de LPL (p=0,01), que correlacionaron entre si (r=0,38; p=0,01; ajustado por HOMA-IR y cintura: β=0,35; p=0,02). ADP correlacionó negativamente con AGL y %-VLDL grandes (p<0,03). Se concluye que en SMet la disminución de ADP favorecería la secreción de VLDL sobre-enriquecidas en triglicéridos y de mayor tamaño, y además retardaría el catabolismo de VLDL mediado por LPL, resultando en la acumulación de VLDL alteradas en circulación con características aterogénicas.

The aim of the work was to evaluate whether the reduction of adiponectin (ADP) in metabolic syndrome (MetS) affects the atherogenic features of VLDL. A total of 45 patients with MetS (ATPIII) and 15 healthy controls were studied. In fasting serum, lipid profile, free fatty acids (FFA) and ADP were determined. VLDL was isolated (d<1.006 g/L) and characterized in chemical composition and size (size exclusion-HPLC). In post-heparin plasma, lipoprotein lipase (LPL) activity was measured. In MetS, VLDL showed increased total mass, particle number, VLDL-triglyceride content and higher large-VLDL proportion (p<0.05). The increase in FFA correlated with VLDL mass (r=0.36; p=0.009), VLDL particle number (r=0.45; p=0.0006) and large-VLDL proportion (r=0.32; p=0.02). MetS patients showed a decrease in ADP (7.4±4.8 vs. 15.5±7.2 μg/mL, p=0.01) and in LPL activity (p=0.01), that positively correlated between them (r=0.38; p=0.01; adjusted by HOMA-IR and waist: β=0.35; p=0.02). ADP inversely correlated with FFA and large-VLDL% (p<0.03). It can be concluded that in MetS, decreased ADP would favour the secretion of triglyceride over-enriched and larger VLDL particles, and also would delay VLDL catabolism mediated by LPL, resulting in the accumulation of altered VLDL with atherogenic characteristics.

O objetivo do trabalho foi avaliar se a redução da adiponectina (ADP) na síndrome metabólica (SM), afeta as características aterogênicas das VLDL. Foram estudados 45 indivíduos com SM e 15 controles saudáveis. Em jejum, foi medido em soro o perfil lipídico, ácidos graxos livres (AGL) e ADP. Foram isoladas as VLDL (d <1,006 g / L) caracterizando-as em relação a sua composição química e tamanho (HPLC- exclusão molecular). No plasma pós-heparina foi medida a atividade da lipoproteína lipase (LPL). Em indivíduos com SM, as VLDL apresentaram aumento de massa, número de partículas, conteúdo de triglicerídeos -VLDL e maior proporção de VLDL grandes (p<0,05). O aumento de AGL correlacionou com a massa de VLDL (r=0,36; p=0,009), número de partículas -VLDL (r=0,45; p=0,0006) e percentual -VLDL grandes (r=0,32; p=0,02). A SM mostrou uma diminuição em ADP (7,4±4,8 vs. 15,5±7,2 μg/mL, p=0,01) e em atividade de LPL (p=0,01), que correlacionaram entre eles (r=0,38; p=0,01; ajustada por HOMA-IR e cintura: β=0,35; p=0,02). A ADP correlacionou em forma negativa com AGL e %-VLDL grandes (p<0,03). A conclusão é que em indivíduos com SM, a diminuição da ADP iria favorecer a secreção de VLDL super-enriquecidas em triglicerídeos e de maior tamanho, e também atrasaria o catabolismo das VLDL mediado por LPL, resultando na acumulação de VLDL alteradas em circulação com características aterogênicas.

Alterations in triglyceride rich lipoproteins are related to endothelial dysfunction in metabolic syndrome.

UNLABELLED: Our aim was to analyze the effect of circulating triglyceride rich lipoprotein (TRL) on endothelial function in metabolic syndrome (MetS). METHODS: We studied 40 patients with MetS (ATPIII), divided into those presenting normal endothelial function (n=19) and those with endothelial dysfunction (n=21) by means of the evaluation of pulse wave velocity, before and after brachial artery ischemia. In fasting serum we measured lipid and lipoprotein profile, insulin and glucose (HOMA-IR). Moreover, isolated TRL (d<1006g/l) were chemically characterized. In parallel, using randomly selected TRL from MetS patients with endothelial dysfunction (n=6) and MetS patients with normal endothelial function (n=6), the ability of TRL to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously pre-contracted by noradrenaline (10(-8)mM) was evaluated. RESULTS: Interestingly, TRL isolated from MetS patients presenting endothelial dysfunction showed triglyceride over-enrichment (59.1±4.8 vs. 54.1±4.7%; p=0.04), even after adjusting by potential confounders (p=0.05). In addition, while TRL resulting from both MetS groups significantly inhibited endothelium dependent vasorelaxation (p<0.001), TRL from MetS patients with endothelial dysfunction showed a strong tendency to a greater inhibition of vasorelaxation (p=0.06). Moreover, TRL-triglyceride (%) showed a strong tendency to correlate with the grade of vasorelaxation inhibition exerted by TRL (r=0.60; p=0.05). CONCLUSION: These results, taken together, would allow inferring for the first time that the predominance of triglyceride over-enriched TRL in circulation in MetS would induce endothelial dysfunction, contributing to the inherent cardiovascular risk of MetS.

Aceite de girasol alto oleico: hacia la construcción de una grasa saludable / High oleic sunflower oil supplemented: towards the construction of a healthful fat

Introducción: dado que el aceite de girasol alto oleico (AGAO) es una alternativa viable, ampliamente utilizada, planteamos el agregado de fitoesteroles o aceite de pescado como una nueva estrategia nutricional que logre posicionar al AGAO como una fuente de lípidos saludable. Objetivos: evaluar el efecto del enriquecimiento de AGAO con fitoesteroles (AGAO-F) naturales o suplementación con aceite de pescado (AGAO-n3) sobre el perfil lipídico-lipoproteico, la grasa corporal total y la masa ósea, en un modelo experimental de hipercolesterolemia nutricional (HCN) en crecimiento y analizar el beneficio de dicho enriquecimiento/suplementación en relación al aceite de oliva extra virgen (AO). Materiales y métodos: 48 ratas Wistar macho al destete recibieron por tres semanas (T3) una dieta aterogénica rica en grasa saturada (GS) y col para inducir HCN. A T3 se midió la colesterolemia (col-T) y se dividieron en cuatro grupos. Por cinco semanas (T8), se reemplazó GS por AGAO o AGAO-F o AGAO-n3 o AO. Las dietas se administraron ad libitum y se registró zoometría y consumo (kcal/100g peso corporal/día). A T8 se evaluaron: índice hepatosomático (IH, %), col-T, colnoHDL, col-HDL y TG séricos (mg/dL), % grasa corporal total y distribución, densidad (DMOg/cm2 ) y contenido mineral óseo (CMO,g) de esqueleto total (DPX). Resultados: sin diferencias en peso (g), longitud (cm), consumo e IH. AGAO-F mejoró todos los lípidos séricos. AGAO-n3 mostró menores niveles de col-T, col-noHDL (p=0,000); no de TG. Sin diferencias en grasa corporal y CMO; AGAO-n3: menor porcentaje de grasa intestinal (p=0,003) y DMO (p=0,03). Respecto a AO: AGAO-F y AGAO-n3 mejoraron el perfil-lipídico y AGAO-n3 < grasa intestinal. Conclusiones: en relación a AGAO y AO, AGAO-F y AGAOn3 disminuyeron el riesgo cardiometabólico. En relación a la masa ósea, el agregado de fitoesteroles o aceite de pescado no logró en el tiempo estudiado reducir el riesgo de osteopenia/ osteoporosis impuesto por la HCN.

Introduction: our previous studies demonstrated that the replacement of saturated fat by MUFA rich-diets ameliorated some of the alterations induced by saturated fat. Since high oleic sunflower oil (HOSO) constitutes an important source of MUFA and widely distributed in human nutrition, a supplementation of HOSO may prevent osteopenia and cardiovascular risk improving the biochemical profile. Objectives: the effects of replacing dietary saturated fat, by different ω-9MUFA sources supplemented with natural sterols or fish oil, on serum lipoprotein profile, body fat and distribution, bone mineral content and density in growing hypercholesterolemic rats, were studied. Materials and methods: forty eight Wistar rats (aged=21days) were fed "ad libitum" with an atherogenic diet, rich in saturated fat and cholesterol for 3 weeks, to induce hypercholesterolemia. Then, rats were randomly assigned to one of 4 groups, according to the source of oil replacing saturated fat: extra virgin olive oil (OO); HOSO, HOSO plus phytosterols (HOSO-P) or HOSO plus fish-oil (HOSO-F) for 5 weeks. After 3 weeks, zoometrics and diet consumption were recorded; hepatic index (HI), serum lipids, body fat content and distribution, bone mass content (BMC) and density (BMD), were assessed. Results: groups showed no significant differences in zoometrics, diet consumption and HI (p>0,05). HOSO-P rats showed a reduction in T-Chol and nonHDL-Chol and the lowest TG levels; HOSO-F showed lower T-chol and non HDL-chol levels (p=0,000), but not TG. Total body fat and BMC were not different among groups. HOSO-F rats showed the lowest intestinal fat content (p=0,003) and BMD (p=0,03). When compared to OO, HOSO-P and HOSO-F improved serum lipids and additionally, HOSO-F showed a reduction in intestinal fat. Conclusions: The replacement of saturated fat rich-diet by HOSO supplemented with phytosterols or fish oil induces bene- ficial effects on serum lipids and cardiovascular disease. However, they could not prevent the detrimental effects on bone.

Overproduction of altered VLDL in an insulin-resistance rat model: influence of SREBP-1c and PPAR-X / Sobreproducción de VLDL alteradas en un modelo de insulinorresistencia de rata: influencia de SREBP-1c y PPAR-x

Background: In insulin-resistance, VLDL presents alterations that increase its atherogenic potential. The mechanism by which insulin-resistance promotes the production of altered VLDL is still not completely understood. The aim of this study was to evaluate the relationship between the expression of sterol regulatory element binding protein 1c (SREBP-1c) and of peroxisome proliferator-activated receptor-α (PPAR-α), with the features of composition and size of VLDL in an insulin-resistance rat model induced by a sucrose rich diet (SRD). Methods: The study was conducted on 12 male Wistar rats (180 g) receiving SRD (12 weeks) and 12 controls. Lipid profile, free fatty acids, glucose, and insulin were measured. Lipid content in liver and visceral fat were assessed. Isolated VLDL (d < 1.006 g/ml) was characterized by its chemical composition and size by HPLC. The respective hepatic expression of SREBP-1c and PPAR-α was determined (Western blot). Results: As expected, SRD had elevated triglycerides (TG), free fatty acids and insulin levels, and decreased HDL-cholesterol (p < 0.05), together with augmented hepatic and visceral fat (p < 0.05). SRD showed higher VLDL total mass - with increased TG content - and predominance of large VLDL (p < 0.05). SRD showed an increase in SREBP-1c (precursor and mature forms) and decreased PPAR-α expression (p < 0.045). SREBP-1c forms were positively associated with VLDL total mass (p < 0.04), VLDL-TG% (p < 0.019), and large VLDL% (p < 0.002). On the other hand, PPAR-α correlated negatively with VLDL total mass (p = 0.05), VLDL-TG% (p = 0.005), and large VLDL% (p = 0.002). Conclusions: Insulin-resistance, by coordinated activation of SREBP-1c and reduction of PPAR-α, could promote the secretion of larger and TG over-enriched VLDL particles, with greater atherogenic capacity

Introducción: En la insulinorresistencia, la VLDL presenta alteraciones que aumentan su potencial aterogénico. El mecanismo por el cual la insulinorresistencia promueve la producción de VLDL alteradas aún no se comprende completamente. Objetivo: evaluar la relación entre la expresión de la proteína ligadora de elementos reguladores de esteroles-1c (SREBP-1c) y de los receptores activados por factores de proliferación peroxisomal-α (PPAR-α) con las características de composición y tamaño de VLDL en un modelo animal de insulinorresistencia inducida por dieta rica en sacarosa (DRS). Métodos: Estudiamos 12 ratas macho Wistar (180 g) que recibieron DRS (12 semanas) y 12 controles. Se midieron el perfil lipídico, los ácidos grasos libres, la glucosa y la insulina. Se cuantificaron el contenido lipídico hapático y la grasa visceral. Se caracterizó la VLDL aislada (d < 1,006 g/ml) en composición química y tamaño (HPLC). Se determinó la expresión hepática de SREBP-1c y PPAR-α (Western-blot). Resultados: Esperadamente, el grupo DRS presentó elevación de triglicéridos (TG), ácidos grasos libres e insulina y disminución de colesterol-HDL (p < 0,05), junto con incremento de grasa hepática y visceral (p < 0,05). La DRS mostró una mayor masa total de VLDL —con mayor contenido de TG— y predominio de VLDL grandes (p < 0,05). DRS presentó expresión incrementada de SREBP-1c (precursor y maduro) y disminuida de PPAR-α (p < 0,045). Ambas formas de SREBP-1c se correlacionaron positivamente con masa total de VLDL (p < 0,04), TG%-VLDL (p < 0,019) y VLDL-grande % (p < 0,002). Mientras que PPAR-α se correlacionó negativamente con masa total de VLDL (p = 0,05), TG %-VLDL (p = 0,005) y VLDL-grande % (p = 0,002). Conclusiones: La insulinorresistencia, mediante una coordinada activación de SREBP-1c y reducción de PPAR-α, promovería la secreción de partículas de VLDL grandes y sobreenriquecidas en TG, con mayor capacidad aterogénica

Monounsaturated fatty acids-rich diets in hypercholesterolemic-growing rats.

The effects of replacing dietary saturated fat by different monounsaturated fatty acid (ω-9MUFA) sources on serum lipids, body fat and bone in growing hypercholesterolemic rats were studied. Rats received one of the six different diets: AIN-93G (control, C); extra virgin olive oil (OO) + C; high-oleic sunflower oil (HOSO) + C or atherogenic diet (AT) for 8 weeks; the remaining two groups received AT for 3 weeks and then, the saturated fat was replaced by an oil mixture of soybean oil added with OO or HOSO for 5 weeks. Rats consuming MUFA-rich diets showed the highest body fat, hepatic index and epididymal, intestinal and perirenal fat, and triglycerides. T-chol and non-HDL-chol were increased in HOSO rats but decreased in OO rats. Bone mineral content and density were higher in both OO and HOSO groups than in AT rats. This study casts caution to the generalization of the benefits of MUFA for the treatment of hypercholesterolemia.

Overproduction of altered VLDL in an insulin-resistance rat model: Influence of SREBP-1c and PPAR-α.

BACKGROUND: In insulin-resistance, VLDL presents alterations that increase its atherogenic potential. The mechanism by which insulin-resistance promotes the production of altered VLDL is still not completely understood. The aim of this study was to evaluate the relationship between the expression of sterol regulatory element binding protein 1c (SREBP-1c) and of peroxisome proliferator-activated receptor-α (PPAR-α), with the features of composition and size of VLDL in an insulin-resistance rat model induced by a sucrose rich diet (SRD). METHODS: The study was conducted on 12 male Wistar rats (180g) receiving SRD (12 weeks) and 12 controls. Lipid profile, free fatty acids, glucose, and insulin were measured. Lipid content in liver and visceral fat were assessed. Isolated VLDL (d<1.006g/ml) was characterized by its chemical composition and size by HPLC. The respective hepatic expression of SREBP-1c and PPAR-α was determined (Western blot). RESULTS: As expected, SRD had elevated triglycerides (TG), free fatty acids and insulin levels, and decreased HDL-cholesterol (p<0.05), together with augmented hepatic and visceral fat (p<0.05). SRD showed higher VLDL total mass - with increased TG content - and predominance of large VLDL (p<0.05). SRD showed an increase in SREBP-1c (precursor and mature forms) and decreased PPAR-α expression (p<0.045). SREBP-1c forms were positively associated with VLDL total mass (p<0.04), VLDL-TG% (p<0.019), and large VLDL% (p<0.002). On the other hand, PPAR-α correlated negatively with VLDL total mass (p=0.05), VLDL-TG% (p=0.005), and large VLDL% (p=0.002). CONCLUSIONS: Insulin-resistance, by coordinated activation of SREBP-1c and reduction of PPAR-α, could promote the secretion of larger and TG over-enriched VLDL particles, with greater atherogenic capacity.

Atherogenic cholesterol-rich diet and periodontal disease.

OBJECTIVE: This study investigated the effect of an atherogenic cholesterol-rich diet (AT) on the alveolar bone loss in rats with ligature-induced experimental periodontitis (EP). METHODS: Female Wistar adult rats were assigned either a control (Co) or an AT diet fed for 9 weeks. The AT diet was high in saturated fat, cholesterol and energy. At week 2, animals were subjected to a unilateral ligature (L) around the left first molar (Co+L and AT+L). The contra lateral first right molar (not ligated) of both groups (Co and AT) were used as untreated controls. At week 9, blood was drawn, rats were euthanized, hemi-mandibles removed and stained digital photographs (buccal and lingual surfaces) and radiographs were obtained for quantification of alveolar bone loss (ABL). The ABL was determined by distance and area methods (mm(2)) and X-rays were used for periodontal bone support (PBS), (%). RESULTS: Rats in the AT group exhibited a 17% increase in energy intake, gained significant body weight and showed the highest serum total-cholesterol (T-C) and non-high density lipoprotein-cholesterol (HDL-C) levels (p<0.001). The amount of lost periodontal bone was the greatest in AT+L rats. AT feedings significantly increased the buccal area and distance of bone loss when compared with the unligated-teeth (p<0.001). The rats in the AT+L group also achieved the lowest percentage of PBS (p<0.001). The AT and Co+L rats showed similar PBS. This method more clearly elucidated the effect of the cholesterol-rich AT, with and without the influence of molar ligature, compared to the morphometric analysis. CONCLUSION: The alveolar bone loss of EP was magnified by ingestion of an atherogenic diet high in saturated fatty acids and cholesterol.

Role of HDL in neutralizing the VLDL effect on endothelial dysfunction.

OBJECTIVE: It has been reported that LDL inhibits endothelium-dependent relaxation (EDR) and that HDL can neutralize this effect. However, the atherogenic properties of VLDL have been so far difficult to demonstrate. Studies on VLDL are controversial, and nothing is known about the role of HDL on potential VLDL vascular actions. We examined the effect of human VLDLs on EDR, and the role of HDL in this system. METHODS: VLDL (n=14) and LDL (n=6) were isolated from volunteer subjects. Normal HDL was obtained from one healthy donor. VLDL ability to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously precontracted by noradrenaline (10(-8)mM) was measured in the presence and absence of HDL. RESULTS: ACh-induced maximal relaxation (R%) was mildly, but not significantly attenuated in the presence of VLDL (72±7%), while LDL caused a significant inhibition (60±10%, p<0.05) when compared to incubation in the absence of lipoproteins. VLDLs were subdivided into 2 groups depending on their cholesterol/triglyceride ratio: 0.18-0.22 (n=8) was considered typical and 0.10-0.15, rich in triglycerides (VLDLRT, n=6). Typical VLDL had no effect on EDR (p=0.38), however R% from VLDLRT was lower (54±7%, p<0.01) similar to the one obtained with LDL (p=0.32). HDL showed favorable effects on EDR inhibition induced by the presence of VLDLRT (p<0.05.). CONCLUSION: Although typical VLDL did not cause endothelial dysfunction, triglyceride-enriched VLDL had inhibitory effect on EDR. It is proposed that alterations in VLDL composition would increase its atherogenic capacity. Moreover HDL appears to protect endothelium from VLDL action.