PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression

The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers.

Results The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects.

Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus. Conclusion Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD.