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

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Abstract Background and aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common liver disease worldwide. This study investigates how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), impacts MASLD. Methods 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 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 underscored by reduced liver steatosis in all the mouse models. Both long-term models showed improvements in body weight and liver morphology, alongside reductions in inflammation and fibrosis. Additionally, tumor formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα’s activity, likely 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 an essential component 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 comprehensively supports that dual nuclear receptor targeting by simultaneously increasing PPARα and diminishing ERRα activity may represent a viable novel strategy against MASLD. Lay summary Our study using three distinct MASLD mouse models shows that a simultaneous targeting of PPARα and ERRα reduces liver fat, fibrosis, inflammation, and tumor formation. The combination treatment modifies lipid metabolism pathways, and uniquely lowers levels of serum amyloid A1/A2 in the liver. Impact and implications Our research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPARα activity while diminishing ERRα activity. With PPARα agonists already tested in phase III clinical trials, ERRα ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.

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