Moderate-intensity continuous training reduces triglyceridemia and improves oxygen consumption in dyslipidemic apoCIII transgenic mice

This study aimed to investigate metabolism modulation and dyslipidemia in genetic dyslipidemic mice through physical exercise. Thirty-four male C57Bl/6 mice aged 15 months were divided into non-transgenic (NTG) and transgenic overexpressing apoCIII (CIII) groups. After treadmill adaptation, the trained groups (NTG Ex and CIII Ex) underwent an effort test to determine running performance and assess oxygen consumption (V̇O2), before and after the training protocol. The exercised groups went through an 8-week moderate-intensity continuous training (MICT) program, consisting of 40 min of treadmill running at 60% of the peak velocity achieved in the test, three times per week. At the end of the training, animals were euthanized, and tissue samples were collected for ex vivo analysis. ApoCIII overexpression led to hypertriglyceridemia (P<0.0001) and higher concentrations of total plasma cholesterol (P<0.05), low-density lipoprotein (LDL) cholesterol (P<0.01), and very low-density lipoprotein (VLDL) cholesterol (P<0.0001) in the animals. Furthermore, the transgenic mice exhibited increased adipose mass (P<0.05) and higher V̇O2peak compared to their NTG controls (P<0.0001). Following the exercise protocol, MICT decreased triglyceridemia and cholesterol levels in dyslipidemic animals (P<0.05), and reduced adipocyte size (P<0.05), increased muscular glycogen (P<0.001), and improved V̇O2 in all trained animals (P<0.0001). These findings contribute to our understanding of the effects of moderate and continuous exercise training, a feasible non-pharmacological intervention, on the metabolic profile of genetically dyslipidemic subjects.

Lean adolescents with insulin resistance display higher angiopoietin like protein 3, ApoC-III and chylomicron remnant dyslipidemia.

BACKGROUND: Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity. METHODS: This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42). RESULTS: As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C c, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant. CONCLUSION: Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).

[Familial chylomicronemia]. / Quilomicronemia familiar.

Familial chylomicronemia is a disease in which a genetic mutation affects the ability of the organism to metabolize triglycerides bound to lipoproteins, causing extremely high plasma triglycerides and associated consequences. The most frequent complication is acute pancreatitis, which may lead to multiorganic failure or pancreatic insufficiency. Familial chylomicronemia also exerts a profound negative impact on quality of life, social relationships and professional development. The gene most frequently affected is lipoprotein lipase-1 gene (LPL), the enzyme in charge of hydrolyzing circulating triglycerides for tissue uptake. Mutations in other genes regulating maturation, transport or polymerization (eg. APOC2, APOAV, LMF-1, GPIHBP-1) of lipoprotein lipase-1, may also be involved. However, in about 30% of patients the causal variant is not identified. Familial chylomicronemia should be suspected in patients with severe hypertriglyceridemia with poor response to conventional treatment, or accompanied by eruptive xanthomas, lipemia retinalis or abdominal pain. The availability of risk scores and genetic tests should facilitate its opportune detection and management. Nutritional therapy is based on a very-low-fat diet with adequate supply of lipid-soluble vitamins and essential fatty acids, plus avoidance of alcohol consumption. Current pharmacological treatment may include fibrates and omega-3 fatty acids but prioritizes biotechnological agents targeting the molecular disturbances of the disease. These include an antisense oligonucleotide against apoC-III (volanesorsen), a monoclonal antibody against angiopoietin-like protein-3 (evinacumab), and other agents currently in development.

La quilomicronemia familiar es una condición en que una mutación genética altera la capacidad de metabolizar los triglicéridos que viajan en las lipoproteínas, causando elevación extrema de triglicéridos plasmáticos y complicaciones asociadas. La complicación más frecuente es la pancreatitis, que puede llevar a falla multiorgánica o insuficiencia pancreática. La quilomicronemia familiar también afecta la calidad de vida, las relaciones sociales y el desarrollo profesional. El gen más frecuentemente afectado en la quilomicronemia familiar es el de lipoproteína lipasa-1 (LPL), enzima que hidroliza triglicéridos circulantes para su captación tisular. Mutaciones en genes (como APOC2, APOAV, LMF-1, GPIHBP-1) que codifican para proteínas que regulan la maduración, transporte o polimerización de lipoproteína lipasa-1, también pueden estar involucradas. Sin embargo, en cerca del 30% de los pacientes no se encuentra la variante causal. La quilomicronemia familiar debe sospecharse en casos de hipertrigliceridemia extrema, resistente al tratamiento convencional, o que se acompaña de xantomas eruptivos, lipemia retinalis o dolor abdominal. La disponibilidad de escalas de riesgo y pruebas genéticas deben promover la detección oportuna. La nutrición se basa en una dieta muy baja en grasa con adecuada suplencia de vitaminas liposolubles y ácidos grasos esenciales, además de evitar el consumo de alcohol. Si bien el tratamiento farmacológico incluye fibratos y ácidos grasos omega 3, el enfoque actual privilegia agentes biotecnológicos dirigidos a los defectos moleculares propios de la enfermedad. Ello incluye un oligonucleótido antisentido dirigido contra apoC-III (volanesorsen), un anticuerpo monoclonal contra la proteína similar a angiopoietina tipo 3 (evinacumab), y otros compuestos en desarrollo.

Quilomicronemia familiar / Familial chylomicronemia

Resumen La quilomicronemia familiar es una condición en que una mutación genética altera la capacidad de metabolizar los triglicéridos que viajan en las lipoproteínas, causando elevación extrema de triglicéridos plasmáticos y complicaciones asociadas. La complicación más frecuente es la pancreatitis, que puede llevar a falla multiorgánica o insuficiencia pancreática. La quilomicronemia familiar también afecta la calidad de vida, las relaciones sociales y el desarrollo profesional. El gen más frecuentemente afectado en la quilomicronemia familiar es el de lipoproteína lipasa-1 (LPL), enzima que hidroliza triglicéridos circulantes para su captación tisular. Mutaciones en genes (como APOC2, APOAV, LMF-1, GPIHBP-1) que codifican para proteínas que regulan la maduración, transporte o polimerización de lipoproteína lipasa-1, también pueden estar involucradas. Sin embargo, en cerca del 30% de los pacientes no se encuentra la variante causal. La quilomicronemia familiar debe sospecharse en casos de hipertrigliceridemia extrema, resistente al tratamiento convencional, o que se acompaña de xantomas eruptivos, lipemia retinalis o dolor abdominal. La disponibilidad de escalas de riesgo y pruebas genéticas deben promover la detección oportuna. La nutrición se basa en una dieta muy baja en grasa con adecuada suplencia de vitaminas liposolubles y ácidos grasos esenciales, además de evitar el consumo de alcohol. Si bien el tratamiento farmacológico incluye fibratos y ácidos grasos omega 3, el enfoque actual privilegia agentes biotecnológicos dirigidos a los defectos moleculares propios de la enfermedad. Ello incluye un oligonucleótido antisentido dirigido contra apoC-III (volanesorsen), un anticuerpo monoclonal contra la proteína similar a angiopoietina tipo 3 (evinacumab), y otros compuestos en desarrollo.

Abstract Familial chylomicronemia is a disease in which a genetic mutation affects the ability of the organism to metabolize triglycerides bound to lipoproteins, causing extremely high plasma triglycerides and associated consequences. The most frequent complication is acute pancreatitis, which may lead to multiorganic failure or pancreatic insufficiency. Familial chylomicronemia also exerts a profound negative impact on quality of life, social relationships and professional development. The gene most frequently affected is lipoprotein lipase-1 gene (LPL), the enzyme in charge of hydrolyzing circulating triglycerides for tissue uptake. Mutations in other genes regulating maturation, transport or polymerization (eg. APOC2, APOAV, LMF-1, GPIHBP-1) of lipoprotein lipase-1, may also be involved. However, in about 30% of patients the causal variant is not identified. Familial chylomicronemia should be suspected in patients with severe hypertriglyceridemia with poor response to conventional treatment, or accompanied by eruptive xanthomas, lipemia retinalis or abdominal pain. The availability of risk scores and genetic tests should facilitate its opportune detection and management. Nutritional therapy is based on a very-low-fat diet with adequate supply of lipid-soluble vitamins and essential fatty acids, plus avoidance of alcohol consumption. Current pharmacological treatment may include fibrates and omega-3 fatty acids but prioritizes biotechnological agents targeting the molecular disturbances of the disease. These include an antisense oligonucleotide against apoC-III (volanesorsen), a monoclonal antibody against angiopoietin-like protein-3 (evinacumab), and other agents currently in development.