Hepatocyte-specific PPARγ Deletion Uncovers Role of an Antagonistic PPARγ–HNF4α Transcriptional Axis in Metabolic Dysfunction–Associated Steatotic Liver Disease Progression

Systemic peroxisome proliferator-activated receptor gamma (PPARγ) agonist therapies have been investigated for clinical use in metabolic dysfunction-associated steatotic liver disease (MASLD). Previous studies, however, have shown that PPARγ activation in hepatocytes worsens MASLD. Overall, the precise molecular mechanisms regulated by PPARγ in hepatocytes during MASLD remain incompletely defined. Hepatocyte-specific PPARγ knockout mice were fed a clinically relevant fast-food diet for 2 or 5 months to characterize the role of PPARγ in MASLD progression. PPARγ expression and activity were increased in the murine fast-food diet model and in hepatocytes of patients with MASLD. PPARγ deletion protected against steatosis, fibrosis, and liver injury by suppressing lipogenic, inflammatory, and fibrogenic signaling. While de novo fatty acid synthesis pathway was only modestly altered and compensated with disease progression, effects on lipid droplet remodeling were persistent. PPARγ deletion consistently inhibited signaling of transforming growth factor-β1, a key driver of fibrosis. Importantly, a novel PPARγ-hepatocyte nuclear factor 4α (HNF4α) regulatory axis in MASLD was identified, with increased HNF4α mRNA/protein expression and activation of its downstream networks in PPARγ-deficient livers. Integrated chromatin immunoprecipitation sequencing and transcriptomics analysis suggests that HNF4α co-regulates over 70% of PPARγ target genes during MASLD. This study provides a comprehensive temporal framework for hepatocyte PPARγ function in MASLD, and reveals an antagonistic PPARγ-HNF4α transcriptional network governing hepatic metabolism.