Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis

Abstract

Dysregulated hepatocyte lipid metabolism is a hallmark of hepatic lipotoxicity and contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl CoA carboxylase (ACC) inhibitors decrease hepatocyte lipotoxicity by inhibiting de novo lipogenesis and concomitantly increasing fatty acid oxidation (FAO), and firsocostat, a liver‐targeted inhibitor of ACC1/2, is under evaluation clinically in patients with NASH. ACC inhibition is associated with improvements in indices of NASH and reduced liver triglyceride (TG) content, but also increased circulating TG in subjects with NASH and preclinical rodent models. Here we evaluated whether enhancing hepatocyte FAO by combining ACC inhibitors with peroxisomal proliferator‐activated receptor (PPAR) or thyroid hormone receptor beta (THRβ) agonists could drive greater liver TG reduction and NASH/antifibrotic efficacy, while ameliorating ACC inhibitor–induced hypertriglyceridemia. In high‐fat diet–fed dyslipidemic rats, the addition of PPAR agonists fenofibrate (Feno), elafibranor (Ela), lanifibranor (Lani), seladelpar (Sela) or saroglitazar (Saro), or the THRb agonist resmetirom (Res), to an analogue of firsocostat (ACCi) prevented ACCi‐induced hypertriglyceridemia. However, only PPARα agonists (Feno and Ela) and Res provided additional liver TG reduction. In the choline‐deficient high‐fat diet rat model of advanced liver fibrosis, neither PPARα (Feno) nor THRβ (Res) agonism augmented the antifibrotic efficacy of ACCi. Conclusion : These data suggest that combination therapies targeting hepatocyte lipid metabolism may have beneficial effects on liver TG reduction; however, they may not be sufficient to drive fibrosis regression.

A Study to Evaluate the Efficacy of Saroglitazar in Non-Alcoholic Steatohepatitis Induced by High Fructose Diet Rat Model

“…26 The use of acetyl CoA carboxylase inhibitors as an augmented form of treatment alongside PPAR agonists has also been studied and further research could help produce better outcomes in patients suffering from NASH. 27 The current study has determined the therapeutic benefits of saroglitazar for the treatment of NASH using an animal model. Thus, the study has added to the scientific evidence for the potent therapeutic role of saroglitazar in NASH treatment.…”

“…The use of acetyl CoA carboxylase inhibitors as an augmented form of treatment alongside PPAR agonists has also been studied and further research could help produce better outcomes in patients suffering from NASH. 27…”

Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis

“…For conventional light microscopy, livers were fixed in 4% neutral buffered formaldehyde solution for 24 h, embedded in paraffin, and stained with H&E or PSR 18 and F4/80 19 as described. Hydroxyproline was measured biochemically and normalized to liver weight using cryo-powdered livers as described.…”

Hepatocyte-specific miR-33 deletion attenuates NAFLD-NASH-HCC progression

“…A coordinated regulation of these processes is necessary to properly boost mitochondrial activity without detrimental effects associated with mitochondrial-derived oxidative stress and reactive oxygen species (ROS) formation. On the other hand, targeting de novo lipogenesis (DNL) has also arisen as a therapeutic option to temper NAFLD pathogenesis (27)(28)(29)(30). Therefore, due to its complexity and the necessity to hit multiple pathways (15,31), combination therapies may be the most effective approaches to treat NAFLD MicroRNAs (miRNAs) have shown great promise as potential therapeutic targets for the treatment of metabolic disease, due to their ability to target many mRNAs and pathways simultaneously (32,33).…”