Bempedoic acid (BemA) is an ATP-citrate lyase (ACLY) inhibitor used to treat hypercholesterolemia. We studied the anti-steatotic effect of BemA, and the mechanisms involved, in a model of fatty liver in female rats obtained through the administration of a high-fat diet supplemented with liquid fructose (HFHFr) for three months. In the third month, a group of rats was treated with BemA (30 mg/kg/day) by gavage. Plasma analytes, liver histology, adiposity, and the expression of key genes controlling fatty acid metabolism were determined, and PPAR agonism was explored by using luciferase reporter assays. Our results showed that, compared to HFHFr, BemA-treated rats exhibited lower body weight, higher liver/body weight, and reduced hepatic steatosis. In addition to ACLY inhibition, we found three novel mechanisms that could account for the anti-steatotic effect: (1) reduction of liver ketohexokinase, leading to lower fructose intake and reduced de novo lipogenesis; (2) increased expression of patatin-like phospholipase domain-containing protein 3, a protein related to the export of liver triglycerides to blood; and (3) PPARα agonist activity, leading to increased hepatic fatty acid β-oxidation. In conclusion, BemA may represent a novel approach to treat hepatic steatosis, and therefore to avoid progression to advanced stages of non-alcoholic fatty liver disease.
To read the full article click HERE.
Date of publication: 27 June 2022; Biomedicines, 2022 10(7)
Author information: Nicola Evans (1), Justin M. Conley (1), Mary Cardon (1), Phillip Hartig (1), Elizabeth Medlock-Kakaley (1), L. Earl Gray Jr. (1) Ana Magdalena Velázquez (1), Roger Bentanachs (1), Aleix Sala-Vila (2), Iolanda Lázaro (2), Jose Rodríguez-Morató (3,4,5), Rosa María Sánchez (1,5,6), Juan Carlos Laguna (1,5,6), Núria Roglans (1,5,6), Marta Alegret (1,5,6)
(1) Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain
(2) Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain
(3) Integrative Pharmacology and Systems Neuroscience Research Group, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, 08003 Barcelona, Spain
(4) Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain
(5) Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
(6) Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain