PPARalpha-ERRalpha crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression
Background and aimsMetabolic 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 (PPAR) and estrogen-related receptor alpha (ERR), impacts MASLD. MethodsThe PPAR agonist pemafibrate and/or ERR 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. ResultsThe 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 ERR inhibits PPARs activity, likely explaining why ERR 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 treatments effectiveness. MASLD/MASH patient livers showed reduced PPAR and increased ERR levels supporting disrupted NR crosstalk in the hepatocyte nucleus. ConclusionOur study comprehensively supports that dual nuclear receptor targeting by simultaneously increasing PPAR and diminishing ERR activity may represent a viable novel strategy against MASLD. Lay summaryOur study using three distinct MASLD mouse models shows that a simultaneous targeting of PPAR and ERR 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 implicationsOur research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPAR activity while diminishing ERR activity. With PPAR agonists already tested in phase III clinical trials, ERR ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.