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.