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

Abstract

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates 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 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.

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.