KHK, PNPLA3 and PPAR as novel targets for the anti-steatotic action of bempedoic acid

Abstract

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.

This research was supported by grant SAF2017-82369-R funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe”, grant PID2020-112870RB-I00 funded by MCIN/AEI/10.13039/501100011033, grant 2017 SGR 38 from Generalitat de Catalunya, and Basic Research 2020 grant of the Spanish Atherosclerosis Society. A.M.V. and R.B are predoctoral fellows (BECAL program BCAL04-327, from the Government of Paraguay, and PREDOCS-UB, from the University of Barcelona, respectively). A.S.-V. is a recipient of the Instituto de Salud Carlos III Miguel Servet fellowship (grant CP II 17/00029).