Hepatocyte-specific PPARγ Deletion Uncovers Role of an Antagonistic PPARγ–HNF4α Transcriptional Axis in MASLD Progression

Although de-novo fatty-acid synthesis was only modestly affected and compensated with disease progression, enhancement of lipolysis and suppression of lipid droplet stabilization machinery was persistent. PPARγ-deletion robustly inhibited expression and signaling-activity of TGFβ1, a master regulator of hepatic ¬fibrosis, throughout the progression of MASLD. Importantly, a novel PPARγ-HNF4α regulatory axis in MASLD was identified, with increased HNF4α mRNA/protein expression and activation of its downstream metabolic networks in PPARγ-deficient livers.

Further, integration of ChIP-seq and transcriptomic analysis revealed that HNF4α might be co-regulating a major fraction (>70%) of genes under direct control of PPARγ during MASLD. This study provides a comprehensive temporal framework for hepatocyte PPARγ function in MASLD, revealing an antagonistic PPARγ-HNF4α transcriptional network that governs hepatic metabolic fate.