Bempedoic acid as a PPARα activator: New perspectives for hepatic steatosis treatment in a female rat experimental model

• Published in: Clínica e investigación en arteriosclerosis (Internet, English ed.) English ed.), 2022-03, Vol.34 (2), p.57-67
• Main Authors: Bentanachs, Roger, Velázquez, Ana Magdalena, Sánchez, Rosa María, Alegret, Marta, Laguna, Juan Carlos, Roglans, Núria
• Format: Article
• Language: English
• Subjects: Bempedoic acid; Dieta grasa; Esteatosis hepática; Fructosa; Fructose; Hepatic steatosis; High-fat diet; Hipertrigliceridemia; Hypertriglyceridemia; PPARα; Ácido bempedoico
• ISSN: 2529-9123; 2529-9123
• DOI: 10.1016/j.artere.2022.03.001

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. 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 (30 mg/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. 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. 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. 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/alternati