ABSTRACT
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.
Subject(s)
Animals , Female , Rats , Health Sciences , Hypertriglyceridemia/prevention & control , Non-alcoholic Fatty Liver Disease , Adenosine Triphosphate/metabolism , Adenosine Triphosphate/pharmacology , Dicarboxylic Acids , Fatty Acids/pharmacology , Liver/metabolism , Models, Theoretical , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR alpha/pharmacologyABSTRACT
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. CONCLUSIONS: Bempedoic acid could be an effective therapy for the treatment of fatty liver and associated cardiovascular risk. Bempedoic acid has other mechanisms of action besides the inhibition of ATP: citrate lyase, such as the activation of PPARα, which could explain the reduction in hepatic steatosis and the increase in liver weight observed in animals treated with the drug.
