The pan-PPAR agonist lanifibranor improves markers of cardiometabolic health in patients with NASH independent of weight change

Background and aims: Inhibition of the acetyl-CoA carboxylase (ACC) isoforms ACC1 and ACC2 reduces lipogenesis, stimulates lipid oxidation, and improves histologic features and fibrosis-related biomarkers in non-alcoholic steatohepatitis (NASH).Obeticholic Acid (OCA), as an FXR agonist, reduces bile acid synthesis and regulates lipid metabolism in the liver.We evaluated the effect of an ACC inhibitor (ACCi) and OCA in combination on lipid and amino acid metabolism in the humanized liver of chimeric PXB mice (PhoenixBio, Japan).Method: Adult male PXB mice (n = 10, randomized by blood human albumin concentrations) were administered with ACCi (an analog of firsocostat) and/or OCA (10 mg/kg, QD, PO for both compounds) for 18 days and livers were collected 2 h after the last dose.Untargeted metabolomic profiling of liver tissue was performed at Metabolon, Inc (Morrisville, NC, USA) using a combination of LC-MS methods (1).Results: Humanized liver mice developed spontaneous steatosis due to the lack of FGF19 signalling in the liver as engulfed human hepatocytes did not respond to mouse FGF15.ACCi and OCA combination showed additive effects to reduce neutral lipids (triglycerides, diacylglycerols) and long chain fatty acids, and increase acyl-carnitines and 3-hydroxybutyrate.Although the combination reduced 7-hydroxycholesterol, OCA increased cholesterol and cholesteryl esters alone or in combination with ACCi.Primary and secondary bile acids were mainly decreased by OCA and further reduction was observed in combination.OCA and combination increased N-acetylated amino acids and combination also increased polyamines and nicotinamide adenine dinucleotide hydride.Conclusion: Metabolomic analysis revealed that lipid metabolism and energetic profile were rapidly changed by ACCi or OCA treatment and combination of both agents reduced lipid synthesis and promoted fatty acid oxidation in the liver of humanized mice.These changes are similar to the clinical findings in NASH patients treated with ACCi and FXR agonist combination, and support the utility of humanized mouse model to elucidate molecular pathways mediated by NASH therapies.