Background & aims: This study aimed to assess and compare the effects of the GLP-1 analog liraglutide and the PPARα/δ agonist elafibranor on liver histology and their impact on hepatic lipidome, metabolome, Kupffer and hepatic stellate cell activation in a model of advanced non-alcoholic fatty liver disease (NAFLD).
Methods: Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by 36-week Amylin liver NASH (AMLN) diet (high-fat, fructose and cholesterol) were randomized to receive for 12 weeks: (a) liraglutide (0.4 mg/kg/day s.c.), (b) elafibranor (30 mg/kg/day p.o.) and (c) vehicle. Metabolic status, liver pathology, markers of inflammation, Kupffer and stellate cell activation, and metabolomics/lipidomics were assessed at study completion.
Results: Elafibranor and liraglutide improved weight, insulin sensitivity, glucose homeostasis and NAFLD activity score (pre-to-post biopsy). Elafibranor had a profound effect on hepatic lipidome, demonstrated by reductions in glycerides, increases in phospholipids, and by beneficial regulation of mediators of fatty acid oxidation, inflammation and oxidative stress. Liraglutide had a major impact on inflammatory and fibrogenic markers of Kupffer and hepatic stellate cell activation (Galectin-3, Collagen type I alpha 1, alpha-smooth muscle actin). Liraglutide exerted beneficial effects on bile acid and carbohydrate metabolism, demonstrated by restorations of the concentrations of bile acids, glycogen metabolism by-products and pentoses, thus facilitating glycogen utilization turnover and nucleic acid formation.
Conclusions: Liraglutide and elafibranor robustly but through different pathways improve overall metabolic health and liver status in NAFLD. These data indicate important differences in the respective mechanisms of action and support the notion for their evaluation as combination therapies in the future.
Keywords: GLP-1; NAFLD; PPARa/d; PPARγ; lipidomics; metabolomics; steatosis.
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