RESUMEN

In recent years, novel apoC3 inhibitor therapies for the treatment of hypertriglyceridemia have been developed and assessed through phase II and III clinical trials. The objective of this study was to perform an updated meta-analysis on the impact of new apoC3 inhibitor drugs on triglyceride and apoC3 levels, as well as on the incidence of pancreatitis. We conducted a meta-analysis of randomized, placebo-controlled studies assessing the effects of apoC3 inhibitors therapy (antisense oligonucleotides and small interfering RNA) on triglyceride levels, apoC3 levels, and the occurrence of acute pancreatitis. This meta-analysis was performed according to PRISMA guidelines. The random-effects model was performed. Nine randomized clinical trials (n = 717 patients) were considered eligible for this systematic review. ApoC3 inhibitor drugs were consistently associated with decreased triglyceride levels (MD -57.0%; 95% CI -61.9 to -52.1, I2 82%) and lowered apoC3 values (MD -76; 95% CI -80.1 to -71.8, I2 77%) when compared to placebo. Furthermore, the use of apoC3 inhibitor drugs demonstrated a reduction in the risk of acute pancreatitis (OR 0.11; 95% CI 0.04 to 0.27, I2 0%). The present updated meta-analysis of randomized clinical trials demonstrated that the utilization of apoC3 inhibitors in patients with hypertriglyceridemia correlated with reduced apoC3 and triglyceride levels, along with a decreased risk of acute pancreatitis compared to the placebo.

Asunto(s)

Apolipoproteína C-III , Hipertrigliceridemia , Pancreatitis , Triglicéridos , Humanos , Apolipoproteína C-III/antagonistas & inhibidores , Apolipoproteína C-III/sangre , Hipertrigliceridemia/sangre , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/metabolismo , Pancreatitis/epidemiología , Pancreatitis/metabolismo , Pancreatitis/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Triglicéridos/sangre , Triglicéridos/metabolismo

RESUMEN

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.

Asunto(s)

Dislipidemias , Consumo de Oxígeno , Condicionamiento Físico Animal , Triglicéridos , Animales , Masculino , Ratones , Dislipidemias/metabolismo , Dislipidemias/terapia , Dislipidemias/genética , Hipertrigliceridemia/terapia , Hipertrigliceridemia/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Consumo de Oxígeno/fisiología , Condicionamiento Físico Animal/fisiología , Triglicéridos/sangre

RESUMEN

There is an increasing interest in developing natural herb-infused functional beverages with health benefits; therefore, in this study, we aimed to evaluate the effect of strawberry, blueberry, and strawberry-blueberry blend decoction-based functional beverages on obesity-related metabolic alterations in high-fat and high-fructose diet-fed rats. The administration of the three berry-based beverages for eighteen weeks prevented the development of hypertriglyceridemia in obese rats (1.29-1.78-fold) and hepatic triglyceride accumulation (1.38-1.61-fold), preventing the development of hepatic steatosis. Furthermore, all beverages significantly down-regulated Fasn hepatic expression, whereas the strawberry beverage showed the greatest down-regulation of Acaca, involved in fatty acid de novo synthesis. Moreover, the strawberry beverage showed the most significant up-regulation of hepatic Cpt1 and Acadm (fatty acid ß-oxidation). In contrast, the blueberry beverage showed the most significant down-regulation of hepatic Fatp5 and Cd36 (fatty acid intracellular transport). Nevertheless, no beneficial effect was observed on biometric measurements, adipose tissue composition, and insulin resistance. On the other hand, several urolithins and their derivatives, and other urinary polyphenol metabolites were identified after the strawberry-based beverages supplementation. In contrast, enterolactone was found significantly increase after the intake of blueberry-based beverages. These results demonstrate that functional beverages elaborated with berry fruits prevent diet-induced hypertriglyceridemia and hepatic steatosis by modulating critical genes involved in fatty acid hepatic metabolism.

Asunto(s)

Arándanos Azules (Planta) , Hígado Graso , Fragaria , Hipertrigliceridemia , Ratas , Animales , Metabolismo de los Lípidos , Arándanos Azules (Planta)/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Ácidos Grasos/metabolismo , Hipertrigliceridemia/metabolismo , Bebidas , Dieta Alta en Grasa

RESUMEN

Adipose tissue is a metabolic and endocrine organ, and its adipocytes can synthesize and secrete extracellular vesicles (EVs), thus allowing intercellular communication. EVs are nanoparticles that transport lipids, proteins, metabolites, and nucleic acids (mRNA and microRNAs). MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression. miR-132, miR-26b, and miR-155 are associated with obesity, lipid metabolism and adipogenesis. The aim of this study was to evaluate the enriched EVs fraction containing miRNAs (miR-132, miR-26b, and miR-155) in serum from obese female dogs. Thirty-two neutered females in good general condition were recruited, including 21 obese and 11 healthy controls. The initial evaluation of the females included a general physical examination and laboratory tests. Small EVs (sEVs) were isolated from whole blood by serial centrifugation and ultracentrifugation, and nanoparticle analysis was used to determine the size and concentration of serum sEVs. miRNAs were extracted from sEVs enriched fraction and analyzed by real-time polymerase chain reaction. Obese female dogs with hypertriglyceridemia showed an increase in the sEVs concentration and in the expression of miR-132 and miR-26b in sEVs enriched fraction. No changes were observed in the group of obese female dogs with normal serum biochemical profile and in relation to miR-155 expression. These results suggest that obese female dogs with hypertriglyceridemia may present alterations in sEVs and in the expression of miRNAs related to lipid metabolism and adipogenesis.

Asunto(s)

Vesículas Extracelulares , Hipertrigliceridemia , MicroARNs , Animales , Perros , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Femenino , Hipertrigliceridemia/metabolismo , Lípidos , MicroARNs/metabolismo , Obesidad/genética , Obesidad/metabolismo , ARN Mensajero/metabolismo

RESUMEN

Significance: Altered plasma triglyceride metabolism and changes in dietary fatty acid types and levels are major contributors to the development of metabolic and cardiovascular diseases such as fatty liver disease, obesity, diabetes, and atherosclerosis. Lipid accumulation in visceral adipose tissue and ectopically in other organs, as well as lipid-induced redox imbalance, is connected to mitochondrial dysfunction in a range of oxidative stress-associated metabolic and degenerative disorders. Recent Advances: Successful mitochondrial adaptive responses in the context of hypertriglyceridemia and dietary bioactive polyunsaturated fatty acids contribute to increase body energy expenditure and reduce oxidative stress, thus allowing several cell types to cope with metabolic challenges and stresses. These responses include mitochondrial redox signaling, mild uncoupling, and changes in network dynamic behavior. Critical Issues: Mitochondrial bioenergetics and redox changes in a lipid overload context are relatively well characterized. However, the turning point between adaptive and maladaptive mitochondrial responses remains a critical issue to be elucidated. In addition, the relationship between changes in fusion/fission machinery and mitochondrial function is less well understood. Future Directions: The effective mitochondrial responses described here support the research for new drug design and diet or nutraceutical formulations targeting mitochondrial mild uncoupling and effective quality control as putative strategies for cardiometabolic diseases. Antioxid. Redox Signal. 36, 953-968.

Asunto(s)

Hipertrigliceridemia , Mitocondrias , Respiración de la Célula , Metabolismo Energético , Humanos , Hipertrigliceridemia/metabolismo , Lípidos/farmacología , Mitocondrias/metabolismo

RESUMEN

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Asunto(s)

Proteínas Similares a la Angiopoyetina/genética , Apolipoproteína A-II/genética , Factores de Crecimiento de Fibroblastos/genética , Hiperlipoproteinemia Tipo IV/diagnóstico , Hipertrigliceridemia/diagnóstico , Adulto , Proteína 3 Similar a la Angiopoyetina , Apolipoproteína A-V/genética , Apolipoproteína C-II/genética , Apolipoproteínas B/genética , Diagnóstico Diferencial , Femenino , Humanos , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hiperlipoproteinemia Tipo IV/patología , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patología , Insulina/genética , Lipoproteína Lipasa/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptores de Lipoproteína/genética , Triglicéridos/genética

RESUMEN

Monosodium l-glutamate (MSG)-induced obesity is a useful model for non-alcoholic fatty liver disease (NAFLD) studies. However, there is limited data on its initiation and progression. Thus, this study aimed to characterize the onset of metabolic and histopathological features of NAFLD and its progression to non-alcoholic steatohepatitis (NASH) in this model. To perform this study, Swiss mice pups were neonatally injected with MSG (4 g/kg/day, s.c.) or equiosmolar saline and followed up to 60, 120 or 180 days old. At each age, blood, liver, as well as periepididymal and retroperitoneal fat pads were collected for morphometric, biochemical and histological analyses, the later according to NAFLD activity score. MSG mice presented hypertriglyceridemia and central obesity at all ages, but peripheral insulin-resistance was verified only in 120- and 180-day-old mice. Hepatic total fat and triglycerides content were higher in MSG mice at all ages. Accordingly, histopathological analysis showed that 60-day-old MSG mice had microvesicular steatosis with occasional ballooning, which evolved into NASH from 120 days old. Retroperitoneal fat accumulation was the only variable to independently correlate with NAFLD activity total score upon multivariate analysis (R 2=71.45%). There were no differences in IL-6 and TNF-α serum levels among groups. Overall, this study shows that NAFLD is a precocious outcome in MSG-obese mice, whereas the period comprised between 60 and 120 days old seems to be a crucial metabolic window for comprehending pathophysiological events involved in NAFLD-to-NASH progression in this model.

Asunto(s)

Modelos Animales de Enfermedad , Hipertrigliceridemia/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/complicaciones , Grasa Abdominal/metabolismo , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Animales , Animales Recién Nacidos , Progresión de la Enfermedad , Femenino , Humanos , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/etiología , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/inducido químicamente , Obesidad/metabolismo , Glutamato de Sodio/toxicidad , Adulto Joven

RESUMEN

Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6-12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45-1.69, P = 3.84 × 10-31) and serum triglycerides (TG) (ß = 0.067, P = 4.5 × 10-21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.

Asunto(s)

Aminoácidos/metabolismo , Biomarcadores/metabolismo , Hipertrigliceridemia/diagnóstico , Metaboloma , Obesidad Infantil/complicaciones , Aminoácidos/análisis , Antropometría , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Humanos , Hipertrigliceridemia/epidemiología , Hipertrigliceridemia/etiología , Hipertrigliceridemia/metabolismo , Estudios Longitudinales , Masculino , México/epidemiología , Factores de Riesgo

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is the principal manifestation of liver disease in obesity and metabolic syndrome. By comparing hypertriglyceridemic transgenic mice expressing apolipoprotein (apo) CIII with control nontransgenic (NTg) littermates, we demonstrated that overexpression of apoCIII, independent of a high-fat diet (HFD), produces NAFLD-like features, including increased liver lipid content; decreased antioxidant power; increased expression of TNFα, TNFα receptor, cleaved caspase-1, and interleukin-1ß; decreased expression of adiponectin receptor-2; and increased cell death. This phenotype is aggravated and additional NAFLD features are differentially induced in apoCIII mice fed a HFD. HFD induced glucose intolerance together with increased gluconeogenesis, indicating hepatic insulin resistance. Additionally, the HFD led to marked increases in plasma TNFα (8-fold) and IL-6 (60%) in apoCIII mice. Cell death signaling (Bax/Bcl2), effector (caspase-3), and apoptosis were augmented in apoCIII mice regardless of whether a HFD or a low-fat diet was provided. Fenofibrate treatment reversed several of the effects associated with diet and apoCIII expression but did not normalize inflammatory traits even when liver lipid content was fully corrected. These results indicate that apoCIII and/or hypertriglyceridemia plays a major role in liver inflammation and cell death, which in turn increases susceptibility to and the severity of diet-induced NAFLD.

Asunto(s)

Apolipoproteína C-III/biosíntesis , Hipertrigliceridemia/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Apolipoproteína C-III/metabolismo , Muerte Celular/fisiología , Dieta Alta en Grasa , Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Transgénicos , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

BACKGROUND: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene. METHODS AND RESULTS: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele. CONCLUSIONS: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.

Asunto(s)

Caveolina 1/genética , Glucosa/metabolismo , Resistencia a la Insulina/genética , Metabolismo de los Lípidos/genética , Tejido Adiposo/metabolismo , Adolescente , Adulto , Anciano , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Aldosterona/metabolismo , Animales , Glucemia/efectos de los fármacos , Colesterol/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Eplerenona , Femenino , Frecuencia de los Genes , Homeostasis , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/farmacología , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Receptores de Mineralocorticoides/metabolismo , Resistina/genética , Resistina/metabolismo , Proteínas Plasmáticas de Unión al Retinol/genética , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Espironolactona/análogos & derivados , Espironolactona/farmacología , Triglicéridos/metabolismo , Adulto Joven

RESUMEN

Herein, we investigated whether subdiaphragmatic vagotomy has benefits on obesity, body glucose homeostasis, and insulin secretion in cafeteria (CAF)-obese rats. Wistar rats were fed a standard or CAF diet for 12 weeks. Subsequently, CAF rats were randomly submitted to truncal vagotomy (CAF Vag) or sham operation (CAF Sham). CAF Sham rats were hyperphagic, obese, and presented metabolic disturbances, including hyperinsulinemia, glucose intolerance, insulin resistance, hyperglycemia, and hypertriglyceridemia. Twelve weeks after vagotomy, CAF Vag rats presented reductions in body weight and perigonadal fat stores. Vagotomy did not modify glucose tolerance but normalized fed glycemia, insulinemia, and insulin sensitivity. Isolated islets from CAF Sham rats secreted more insulin in response to the cholinergic agent, carbachol, and when intracellular cyclic adenine monophosphate (cAMP) is enhanced by forskolin or 3-isobutyl-1-methylxanthine. Vagotomy decreased glucose-induced insulin release due to a reduction in the cholinergic action on ß-cells. This effect also normalized islet secretion in response to cAMP. Therefore, vagotomy in rats fed on a CAF-style diet effectively decreases adiposity and restores insulin sensitivity. These effects were mainly associated with the lack of cholinergic action on the endocrine pancreas, which decreases insulinemia and may gradually reduce fat storage and improve insulin sensitivity.

Asunto(s)

Hiperglucemia/cirugía , Hiperinsulinismo/cirugía , Hipertrigliceridemia/cirugía , Obesidad/cirugía , Vagotomía , Nervio Vago/cirugía , 1-Metil-3-Isobutilxantina/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Carbacol/farmacología , Colforsina/farmacología , AMP Cíclico/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Glucosa/metabolismo , Glucosa/farmacología , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Hiperglucemia/patología , Hiperinsulinismo/etiología , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patología , Hipertrigliceridemia/etiología , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patología , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Ratas , Ratas Wistar , Técnicas de Cultivo de Tejidos , Nervio Vago/metabolismo

RESUMEN

The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin ß-subunit (hCGß+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGß+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGß+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGß+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies.

Asunto(s)

Gonadotropina Coriónica Humana de Subunidad beta/metabolismo , Intolerancia a la Glucosa/metabolismo , Hiperinsulinismo/metabolismo , Hiperprolactinemia/metabolismo , Hipertrigliceridemia/metabolismo , Resistencia a la Insulina/fisiología , Animales , Glucemia/metabolismo , Cabergolina , Gonadotropina Coriónica Humana de Subunidad beta/genética , Ergolinas/uso terapéutico , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/genética , Hiperinsulinismo/tratamiento farmacológico , Hiperinsulinismo/genética , Hiperprolactinemia/tratamiento farmacológico , Hiperprolactinemia/genética , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/genética , Insulina/sangre , Ratones , Ratones Transgénicos , Prolactina/sangre , Triglicéridos/sangre

RESUMEN

Some high-carbohydrate diets may lead to obesity and multiple metabolic disorders, including hypertriglyceridemia (HTG). This lipid abnormality is considered an important risk factor for cardiovascular disease and type 2 diabetes. The sweet taste receptor TAS1R2 polymorphism (Ile191Val) has been reported to be associated with carbohydrate intake. The aim of this study was to analyze the association of the TAS1R2 gene polymorphism with carbohydrate intake and HTG among the population of West Mexico. In a cross-sectional study, 441 unrelated subjects were analyzed for TAS1R2 genotypes (Ile/Ile, Ile/Val and Val/Val) by an allelic discrimination assay. Biochemical tests and a three-day food record were assessed. The Val/Val genotype carriers had a higher intake of total carbohydrates, fiber and servings of cereals and vegetables than the other genotype carriers. The Val/Val genotype conferred a higher risk for HTG than the Ile/Val and Ile/Ile genotypes (OR = 3.26, 95%CI 1.35-7.86, p = 0.006 and OR = 2.61, 95%CI 1.12-6.07, p = 0.02, respectively). Furthermore, the Val/Val genotype was associated with approximately 30% higher triglycerides compared with Ile/Val and Ile/Ile genotypes (ß = 44.09, 95%CI 9.94-78.25, p = 0.01 and ß = 45.7, 95%CI 10.85-80.54, p = 0.01, respectively). In conclusion, the Val/Val genotype of TAS1R2 was associated with a higher carbohydrate intake and HTG.

Asunto(s)

Carbohidratos de la Dieta/administración & dosificación , Conducta Alimentaria , Hipertrigliceridemia/genética , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/genética , Papilas Gustativas/metabolismo , Gusto , Adulto , Alelos , Estudios Transversales , Femenino , Genotipo , Humanos , Hipertrigliceridemia/metabolismo , Masculino , México , Persona de Mediana Edad , Receptores Acoplados a Proteínas G/metabolismo , Factores de Riesgo

RESUMEN

OBJECTIVES: To determine the efficacy of 4 g/day fish oil to lower triglycerides and impact lipoprotein particles, inflammation, insulin resistance, coagulation, and thrombosis. STUDY DESIGN: Participants (n = 42, age 14 ± 2 years) with hypertriglyceridemia and low-density lipoprotein (LDL) cholesterol <160 mg/dL were enrolled in a randomized, double-blind, crossover trial comparing 4 g of fish oil daily with placebo. Treatment interval was 8 weeks with a 4-week washout. Lipid profile, lipoprotein particle distribution and size, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, fibrinogen, plasminogen activator inhibitor-1, and thrombin generation were measured. RESULTS: Baseline lipid profile was total cholesterol 194 (5.4) mg/dL (mean [SE]), triglycerides 272 (21) mg/dL, high-density lipoprotein cholesterol 39 (1) mg/dL, and LDL cholesterol 112 (3.7) mg/dl. LDL particle number was 1614 (60) nmol/L, LDL size was 19.9 (1.4) nm, and large very low-density lipoprotein/chylomicron particle number was 9.6 (1.4) nmol/L. Triglycerides decreased on fish oil treatment but the difference was not significant compared with placebo (-52 ± 16 mg/dL vs -16 ± 16 mg/dL). Large very low-density lipoprotein particle number was reduced (-5.83 ± 1.29 nmol/L vs -0.96 ± 1.31 nmol/L; P < .0001). There was no change in LDL particle number or size. There was a trend towards a lower prothrombotic state (lower fibrinogen and plasminogen activator inhibitor-1; .10 > P > .05); no other group differences were seen. CONCLUSIONS: In children, fish oil (4 g/day) lowers triglycerides slightly and may have an antithrombotic effect but has no effect on LDL particles.

Asunto(s)

LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Aceites de Pescado/administración & dosificación , Hipertrigliceridemia/sangre , Hipertrigliceridemia/tratamiento farmacológico , Adolescente , Coagulación Sanguínea/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Femenino , Cardiopatías/etiología , Cardiopatías/prevención & control , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/metabolismo , Inflamación/etiología , Inflamación/prevención & control , Resistencia a la Insulina , Masculino , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/prevención & control , Factores de Riesgo , Trombosis/etiología , Trombosis/prevención & control , Triglicéridos

RESUMEN

Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia.

Asunto(s)

Angiopoyetinas/genética , Apolipoproteínas A/genética , Apolipoproteínas B/genética , Interacción Gen-Ambiente , Hipertrigliceridemia/etiología , Proteínas de la Membrana/genética , Polimorfismo Genético , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Angiopoyetinas/metabolismo , Apolipoproteína A-V , Apolipoproteínas A/metabolismo , Apolipoproteínas B/metabolismo , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Hispánicos o Latinos , Humanos , Hiperlipidemia Familiar Combinada/etiología , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipoproteinemia Tipo III/etiología , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , Hiperlipoproteinemia Tipo IV/etiología , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Indígenas Centroamericanos , Indígenas Norteamericanos , Proteínas de la Membrana/metabolismo , México/etnología , Herencia Multifactorial , Estados Unidos

RESUMEN

Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene.

Asunto(s)

Proteínas de Transferencia de Ésteres de Colesterol/agonistas , Ácidos Fíbricos/uso terapéutico , Aceites de Pescado/uso terapéutico , Hipertrigliceridemia/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Hígado/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Animales , Bezafibrato/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Terapia Combinada , Aceite de Maíz/uso terapéutico , Cruzamientos Genéticos , Suplementos Dietéticos , Femenino , Fenofibrato/uso terapéutico , Gemfibrozilo/uso terapéutico , Hipertrigliceridemia/sangre , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/prevención & control , Hígado/metabolismo , Masculino , Ratones Transgénicos , ARN Mensajero/metabolismo , Distribución Aleatoria

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium L-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression.

Asunto(s)

Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Hígado Graso/metabolismo , Hipertrigliceridemia/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Factores de Transcripción/metabolismo , Animales , Proteínas de Unión al ADN/síntesis química , Hígado Graso/inducido químicamente , Ácido Glucurónico , Hipertrigliceridemia/inducido químicamente , Masculino , Obesidad/inducido químicamente , Estrés Oxidativo , Ratas , Ratas Wistar , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Factores de Transcripción/síntesis química , Proteína 1 de Unión a la X-Box

RESUMEN

OBJECTIVE: This study aimed to identify the prevalence of hypertriglyceridemic waist (HTW) phenotype, and to evaluate its association with metabolic abnormalities in adolescents of low socioeconomic status. METHOD: This was a cross-sectional study with a random sample of 1,076 adolescents between 11 and 17 years, of both genders, from public schools. The participants underwent anthropometric measurements (weight, height, and waist circumference), and levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), non-HDL cholesterol, triglyceride (TG), and fasting glucose were measured. Information regarding the socioeconomic status of the participants' families was obtained. The HTW phenotype was defined by the simultaneous presence of increased waist circumference (≥ 90(th) percentile for age and gender) and serum triglyceride levels (≥ 100mg/dL). A logistic regression analysis was used to evaluate the associations of interest. RESULTS: The prevalence of HTW phenotype was 7.2% among the adolescents, being higher in the presence of obesity (63.4%) and high levels of non-HDL cholesterol (16.6%) and LDL-C (13.7%). The bivariate analysis indicated that, of the metabolic variables, only blood glucose was not associated with the HTW phenotype. Multivariate analysis adjusted for age and gender indicated that the HTW phenotype was positively associated with high non-HDL cholesterol (odds ratio: 7.0; 95% CI: 3.9-12.6) and low HDL-C levels (odds ratio: 2.7; 95% CI: 1.5-4.8). CONCLUSIONS: This study demonstrated that the HTW phenotype was associated with an atherogenic lipid profile, and this phenotype is suggested as a screening tool to identify adolescents with metabolic alterations.

Asunto(s)

Hipertrigliceridemia/epidemiología , Síndrome Metabólico/epidemiología , Obesidad Abdominal/epidemiología , Triglicéridos/metabolismo , Circunferencia de la Cintura , Adolescente , Glucemia/análisis , Índice de Masa Corporal , Niño , Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/metabolismo , Lipoproteínas HDL/sangre , Masculino , Tamizaje Masivo , Síndrome Metabólico/genética , Obesidad Abdominal/diagnóstico , Fenotipo , Prevalencia , Factores de Riesgo , Factores Sexuales , Factores Socioeconómicos , Triglicéridos/sangre

RESUMEN

BACKGROUND: Given that hypomagnesemia is related with hyperglycemia, hypertension, hypertriglyceridemia, and insulin resistance, the objective of this study was to determine whether serum magnesium levels are associated with the metabolically obese normal weight (MONW) and the metabolically healthy obese (MHO) phenotypes. METHODS: Population-based cross-sectional study that enrolled 427 subjects, men and non-pregnant women aged 20 to 65years, to participate in the study. Subjects were allocated into groups with and without obesity; among non-obese individuals, the subgroup of MONW subjects was compared with a control group of healthy normal-weight individuals. Among obese individuals, the subgroup of MHO subjects was compared with a control group of obese subjects who exhibited at least one metabolic abnormality. In the absence of obesity, the presence of fasting hyperglycemia, insulin resistance, hypertriglyceridemia, and/or hypertension defined the presence of MONW phenotype. In the absence of hypertension, insulin resistance and metabolic abnormalities of fasting glucose and triglycerides levels, the phenotypically obese subjects were defined as MHO individuals. RESULTS: The sex-adjusted prevalence of MONW and MHO phenotypes was 40.8% and 27.9%. The multivariate logistic regression model adjusted by family history of diabetes, age, body mass index, and waist-circumference, showed a positive association between hypomagnesemia and the MONW phenotype (OR 6.4; 95%CI 2.3-20.4) and negative relationship between serum magnesium and the MHO phenotype (OR 0.32; 95%CI 0.17-0.61). CONCLUSIONS: Our results show that hypomagnesemia is positively associated with the presence of MONW phenotype, and the normomagnesemia negatively with the MHO phenotype.

Asunto(s)

Peso Corporal/fisiología , Magnesio/sangre , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/metabolismo , Obesidad/epidemiología , Obesidad/metabolismo , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Hiperglucemia/epidemiología , Hiperglucemia/metabolismo , Hipertensión/epidemiología , Hipertensión/metabolismo , Hipertrigliceridemia/epidemiología , Hipertrigliceridemia/metabolismo , Resistencia a la Insulina/fisiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Adulto Joven

RESUMEN

OBJETIVO: O presente estudo objetivou identificar a prevalência do fenótipo cintura hipertrigliceridêmica (CHT) e avaliar sua associação com alterações metabólicas em adolescentes de baixa condição econômica. MÉTODO: Estudo transversal com amostra probabilística de 1.076 adolescentes entre 11 e 17 anos, de ambos os sexos, estudantes de escolas públicas. Os participantes foram submetidos à avaliação antropométrica (peso, altura e circunferência da cintura) e à dosagem dos níveis de colesterol total, LDL-C, HDL-C, colesterol não HDL, triglicérides (TG) e glicemia de jejum. Foram obtidas informações referentes às condições econômicas das famílias dos participantes.O fenótipo CHT foi definido pela presença simultânea da circunferência da cintura aumentada (> percentil 90 por idade e sexo) e dos níveis séricos de triglicérides elevados (> 100 mg/dL). A análise de regressão logística foi utilizada para avaliação das associações de interesse. RESULTADOS: A prevalência do fenótipo CHT foi de 7,2% entre os adolescentes, sendo mais elevada na presença de obesidade (63,4%), do colesterol não HDL (16,6%) e do LDL-C (13,7%) altos. A análise bivariada indicou que, das variáveis metabólicas, apenas a glicemia não se associou ao fenótipo CHT. A análise multivariada, ajustada por sexo e idade, indicou que o fenótipo CHT se associou positivamente com o colesterol não HDL alto (odds ratio, 7,0; IC 95% 3,9-12,6) e com o HDL-C baixo (odds ratio, 2,7; IC 95%, 1,5-4,8). CONCLUSÕES: Este estudo mostrou que o fenótipo CHT se associou com um perfil lipídico aterogênico e sugere esse fenótipo como uma ferramenta de screening que pode ser utilizada para identificar adolescentes com alterações metabólicas.

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OBJECTIVE: This study aimed to identify the prevalence of hypertriglyceridemic waist (HTW) phenotype, and to evaluate its association with metabolic abnormalities in adolescents of low socioeconomic status. METHOD: This was a cross-sectional study with a random sample of 1,076 adolescents between 11 and 17 years, of both genders, from public schools. The participants underwent anthropometric measurements (weight, height, and waist circumference), and levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), non-HDL cholesterol triglyceride (TG), and fasting glucose were measured. Information regarding the socioeconomic status of the participants' families was obtained. The HTW phenotype was defined by the simultaneous presence of increased waist circumference (> 90th percentile for age and gender) and serum triglyceride levels (> 100 mg/dL). A logistic regression analysis was used to evaluate the associations of interest. RESULTS: The prevalence of HTW phenotype was 7.2% among the adolescents, being higher in the presence of obesity (63.4%) and high levels of non-HDL cholesterol (16.6%) and LDL-C (13.7%). The bivariate analysis indicated that, of the metabolic variables, only blood glucose was not associated with the HTW phenotype. Multivariate analysis adjusted for age and gender indicated that the HTW phenotype was positively associated with high non-HDL cholesterol (odds ratio: 7.0; 95% CI: 3.9-12.6) and low HDL-C levels (odds ratio: 2.7; 95% CI: 1.5-4.8). CONCLUSIONS: This study demonstrated that the HTW phenotype was associated with an atherogenic lipid profile, and this phenotype is suggested as a screening tool to identify adolescents with metabolic alterations.

Asunto(s)

Adolescente , Niño , Femenino , Humanos , Masculino , Hipertrigliceridemia/epidemiología , Síndrome Metabólico/epidemiología , Obesidad Abdominal/epidemiología , Triglicéridos/metabolismo , Circunferencia de la Cintura , Índice de Masa Corporal , Glucemia/análisis , Estudios Transversales , Colesterol/sangre , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/metabolismo , Lipoproteínas HDL/sangre , Tamizaje Masivo , Síndrome Metabólico/genética , Obesidad Abdominal/diagnóstico , Fenotipo , Prevalencia , Factores de Riesgo , Factores Sexuales , Factores Socioeconómicos , Triglicéridos/sangre