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3.
Clín. investig. arterioscler. (Ed. impr.) ; 34(2): 57-67, mar.-abr. 2022. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-203150

RESUMO

INTRODUCCIÓN: La enfermedad del hígado graso no alcohólico cursa, en sus fases iniciales, con hipertrigliceridemia y acúmulo de lípidos en el hígado (esteatosis hepática). El ácido bempedoico es un inhibidor de la ATP:citrato liasa que promueve una inhibición dual de la síntesis de colesterol y ácidos grasos. Sin embargo, no se ha investigado su efecto en la prevención/tratamiento de la esteatosis hepática y la hipertrigliceridemia. El objetivo de nuestro trabajo ha sido elucidar si el ácido bempedoico, mediante un mecanismo diferente/alternativo a la inhibición de la ATP:citrato liasa, revierte estas alteraciones metabólicas. DISEÑO EXPERIMENTAL: El estudio se realizó con un modelo animal de rata Sprague-Dawley hembra alimentada, durante 3 meses, con una dieta rica en grasa saturada suplementada con fructosa al 10% (p/v) en el agua de bebida. Se administró, durante el último mes, ácido bempedoico (30mg/kg/día) a un grupo de animales. Se analizaron parámetros zoométricos, se realizaron valoraciones plasmáticas, de expresión génica y proteica en muestras de hígado y se determinó la actividad de unión PPAR-PPRE. RESULTADOS: Nuestro modelo de intervención dietética desarrolló esteatosis hepática e hipertrigliceridemia. A pesar de un aumento en la ingesta calórica total, no se observó un incremento de peso corporal de los animales. La administración de ácido bempedoico redujo significativamente la esteatosis hepática y promovió una marcada hipertrofia de los hepatocitos. Se observó un incremento del 66% en el peso del hígado de los animales tratados con el fármaco, que no se acompañó de modificaciones en los marcadores de inflamación, estrés oxidativo o estrés de retículo endoplasmático. El ácido bempedoico activó el receptor nuclear activado por proliferadores peroxisómicos (PPARα) y sus genes diana.


INTRODUCTION: In its initial stages, nonalcoholic fatty liver disease presents hypertriglyceridemia and accumulation of lipids in the liver (hepatic steatosis). Bempedoic acid is an ATP:citrate lyase inhibitor that promotes a dual inhibition of the synthesis of cholesterol and fatty acids. However, its effect in the prevention / treatment of hepatic steatosis and hypertriglyceridemia has not been investigated. The aim of our work has been to elucidate whether bempedoic acid, through a mechanism other than ATP:citrate lyase inhibition, reverses these metabolic alterations. EXPERIMENTAL DESIGN: The study was carried out in female Sprague-Dawley rats fed, for three months, with a high fat diet supplemented with fructose (10% w/v) in drinking water. During the last month, bempedoic acid (30mg/kg/day) was administered to a group of animals. Zoometric and plasmatic parameters were analyzed, gene and protein expression analysis were performed in liver samples and PPAR-PPRE binding activity was determined. RESULTS: Our interventional model developed hepatic steatosis and hypertriglyceridemia. Despite an increase in total caloric intake, there was no increase in body weight of the animals. The administration of bempedoic acid significantly reduced hepatic steatosis and promoted a marked hepatocyte hypertrophy. There was a 66% increase in the liver weight of the animals treated with the drug that was not accompanied by modifications in the markers of inflammation, oxidative stress, or endoplasmic reticulum stress. Bempedoic acid activated the peroxisome proliferator activated nuclear receptor (PPARα) and its target genes.


Assuntos
Animais , Feminino , Ratos , Ciências da Saúde , Hipertrigliceridemia/prevenção & controle , Hepatopatia Gordurosa não Alcoólica , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Ácidos Dicarboxílicos , Ácidos Graxos/farmacologia , Fígado/metabolismo , Modelos Teóricos , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR alfa/farmacologia
4.
Int. microbiol ; 22(4): 461-470, dic. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-185064

RESUMO

To date, tripartite tricarboxylate transport (TTT) systems are not well characterized in most organisms. To investigate which carbon sources are transported by the TTT system of A. mimigardefordensis DPN7T, single deletion mutants were generated lacking either completely both sets of genes encoding for these transport systems tctABCDE1 and tctABDE2 in the organism or the two genes encoding for the regulatory components of the third chosen TTT system, tctDE3. Deletion of tctABCDE1 (MIM_c39170-MIM_c39210) in Advenella mimigardefordensis strain DPN7T led to inhibition of growth of the cells with citrate indicating that TctABCDE1 is the transport system for the uptake of citrate. Because of the negative phenotype, it was concluded that this deletion cannot be substituted by other transporters encoded in the genome of strain DPN7T. A triple deletion mutant of A. mimigardefordensis lacking both complete TTT transport systems and the regulatory components of the third chosen system (ΔTctABCDE1 ΔTctABDE2 ΔTctDE3) showed a leaky growth with alpha-ketoglutarate in comparison with the wild type. The other investigated TTT (TctABDE3, MIM_c17190-MIM_c17220) is most probably involved in the transport of alpha-ketoglutarate. Additionally, thermoshift assays with TctC1 (MIM_c39190) showed a significant shift in the melting temperature of the protein in the presence of citrate whereas no shift occurred with alpha-ketoglutarate. A dissociation constant Kd for citrate of 41.7 μM was determined. Furthermore, alternative alpha-ketoglutarate transport was investigated via in silico analysis


No disponible


Assuntos
Ácidos Tricarboxílicos/metabolismo , Bordetella/genética , Betaproteobacteria/enzimologia , Propionatos/metabolismo , Succinato-CoA Ligases/metabolismo , Transportadores de Ácidos Dicarboxílicos/genética , Ácidos Dicarboxílicos/metabolismo , Espectrometria de Massas/métodos , Ciclo do Ácido Cítrico , Betaproteobacteria/classificação , Propionatos/química , Succinato-CoA Ligases/genética
5.
J. physiol. biochem ; 71(1): 29-42, mar. 2015. ilus
Artigo em Inglês | IBECS | ID: ibc-133900

RESUMO

High-fat diet (HFD) elevates circulatory fatty acids and influences glucose and fat metabolism.Azelaic acid (AzA), a naturally occurring alpha,ω-dicarboxylic acid in wheat, rye, barley, oat seeds and sorghum, has been reported to exert antidiabetic effects in HFD-induced type 2 diabetes mellitus (T2DM) C57BL/6J mice. The present study was undertaken to identify the genes that are differentially modulated by treatment with AzA in HFD-fed mice. Mice were fed HFD for 10 weeks and subjected to intragastric administration of 80 mg/kg body weight (BW) of AzA daily along with HFD from 11 to 15 weeks. Lipid profile, adipokines and cytokines were examined in the plasma/liver of mice. Whole genome profiling was performed in the liver of mice using microarray and validated by qRT-PCR, Western blot and immunohistochemical analyses. HFD intake resulted in significantly elevated lipids (except high-density lipoproteins), resistin, tumour necrosis factor alpha and interleukin-6 with marked reduction in adiponectin. Administration of AzA to HFD-fed mice significantly restored the lipids, adipokines and cytokines to near normal. Transcript profiling revealed that HFD intake activated the genes involved in stress response, cell cycle regulation and apoptosis. Treatment with AzA caused increased expression of genes involved in reactive oxygen species (ROS) scavenging, receptor-mediated signalling, transcription, protein modification and insulin signal transduction. AzA activates insulin signal molecules leading to insulin sensitivity. The ability of AzA to modulate the expression of these genes supports the notion that AzA is a promising drug candidate for the treatment of insulin resistance associated with T2DM


Assuntos
Ratos , Animais , Dieta Hiperlipídica , Ácidos Dicarboxílicos/farmacocinética , Diabetes Mellitus Tipo 2/fisiopatologia , Expressão Gênica , Genômica , Insulina/metabolismo , Transdução de Sinais/fisiologia
6.
Endocrinol. nutr. (Ed. impr.) ; 53(4): 256-262, abr. 2006.
Artigo em Es | IBECS | ID: ibc-043657

RESUMO

El GLP-1 (glucagon-like peptide-1) es una hormona con carácter de incretina que contribuye al control de la homeostasis de la glucosa, y que por su acción insulinotrópica, insulinotrófica y también insulinomimética, se está considerando para el tratamiento de la diabetes mellitus tipo 2. In vitro, el GLP-1 tiene efectos anabólicos sobre el metabolismo hepático de la glucosa en la rata normal y diabética, y sobre el del músculo y la grasa de la rata y del hombre; en el tejido adiposo, el GLP-1 es, además, lipolítico y lipogénico. En estos 3 tejidos extrapancreáticos, el GLP-1 parece actuar a través de receptores específicos, distintos en estructura y/o vía de señalización del pancreático, sobre los que se ha propuesto un inositolfosfoglicano como posible segundo mensajero. Por otro lado, la respuesta secretora de la célula ß al GLP-1, modulada en condiciones normales por la concentración extracelular de glucosa, está alterada en la diabetes tipo 2, debido, posiblemente, a la imposibilidad de la célula para reconocer a la hexosa; sin embargo, nutrientes no glucídicos, capaces de sortear los defectos específicos de reconocimiento de la célula ß diabética hacia la glucosa, como son los ésteres de ácidos dicarboxílicos, potencian y/o prolongan su acción insulinotrópica. Además, el GLP-1 no sólo ejerce un papel regulador de la ingestión de alimentos, induciendo sensación de saciedad, sino que también parece tener acciones beneficiosas en síndromes de carácter neurodegenerativo central y periférico. En cualquier caso, el valor del papel potencial terapéutico del GLP-1 no sólo en la diabetes sino también en la obesidad y en las enfermedades cardíacas y nerviosas, es un hecho que no se debe ignorar, cuyo mecanismo de acción concreto, no del todo conocido, requiere aclaración


Glucagon-like peptide-1 (GLP-1) is an incretin hormone that contributes to the control of glucose homeostasis. Because of its insulinotropic, insulinotrophic and insulinomimetic actions, it is being considered for the treatment of type 2 diabetes mellitus. In vitro, GLP-1 has anabolic effects on glucose metabolism in the liver of normal and diabetic rats and in rat and human skeletal muscle and fat; moreover, in fat tissue, GLP-1 is also lipolytic and lipogenic. In these three extrapancreatic tissues, GLP-1 seems to act through specific receptors, distinct in structure and/or signaling pathway from pancreatic one, for which an inositolphosphoglycan has been proposed as a possible second messenger. The secretory response of ß cells to GLP-1, modulated in normal conditions by the extracellular glucose concentration, is altered in type 2 diabetes mellitus, possibly due to the inability of the cell to recognize the hexose; however, non-glucose nutrients able to bypass the specific hexose recognition defects of the diabetic ß cell, such as dicarboxylic acid esters, potentiate and/or prolong the insulinotropic action of GLP-1. Moreover, GLP-1 not only plays a regulatory role in food intake, by inducing satiety, but also seems to have beneficial effects on central and peripheral neurodegenerative syndromes. The value of the potential therapeutic role of GLP-1, not only in diabetes but also in obesity and cardiac and central nervous system diseases, should not be ignored, and its mechanism of action, which is not clearly understood, requires elucidation


Assuntos
Ratos , Animais , Peptídeos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Obesidade/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Ácidos Dicarboxílicos , Ilhotas Pancreáticas
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