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

ABSTRACT: Systemic PPARγ agonist therapies have been investigated for clinical use in MASLD. Previous studies, however, have shown that PPARγ activation in hepatocytes worsens MASLD. Overall, the precise molecular mechanisms regulated by PPARγ in hepatocyte during MASLD remain incompletely defined. Hepatocyte-specific PPARγ knockout mice were fed a clinically-relevant fast-food diet (FFD) for 2 or 5-months to characterize the role of PPARγ in MASLD progression. PPARγ expression and activity were increased in murine FFD-model and in hepatocytes of human MASLD/MASH patients, based on single-nucleus RNA-sequencing analysis. PPARγ-deletion conferred protection against diet-induced steatosis, fibrosis, and liver injury by suppressing lipogenic, inflammatory, and fibrogenic signaling. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE328680 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

Project description:<p>Type 2 diabetes mellitus (T2DM) with metabolic syndrome-associated steatohepatitis (MASLD) is a complex metabolic comorbidity characterized by hyperglycemia, pancreatic β-cell dysfunction, and hepatic lipid metabolism disorders, in which gut microbiota dysbiosis and abnormal PPARγ signaling play pivotal roles. Zhaqu Compound (ZQC), a traditional Chinese herbal formula, has demonstrated clinical efficacy in improving glucose and lipid metabolism, though its mechanisms remain unclear. In this study, db/db mice with T2DM-MASLD were treated for 12 weeks with ZQC, metformin, or saline, and metabolic outcomes were evaluated via blood glucose, lipid profiles, hepatic lipid accumulation, hepatocyte ultrastructure, gut microbiota (16S rRNA), non-targeted metabolomics, and liver transcriptomics. In high-glucose + palmitate-induced HepG2 cells, ZQC-containing serum and the PPARγ agonist GW1929 were applied, and Western blot was used to assess key gluconeogenic and lipogenic proteins. LC-MS, network pharmacology, and molecular docking identified major ZQC components and their potential interactions with PPARγ. ZQC improved glycemia, insulin resistance, and lipid profiles, and alleviated hepatic steatosis. It increased beneficial gut bacteria (Bacteroidetes, Lactobacillales) and partially restored Lachnospiraceae and Muribaculaceae, modulated amino acid metabolism and AGE-RAGE/mTOR pathways, and activated hepatic PPARγ signaling while regulating fatty acid and arachidonic acid metabolism. In HepG2 cells, ZQC reduced lipid droplet accumulation, lowered triglyceride and total cholesterol levels, enhanced glucose uptake, downregulated key gluconeogenic and lipogenic proteins, and moderately decreased PPARγ and its downstream transporters (CD36, FABP4). N-phenethylhexadecanamide, palmitic acid, and isoflavone likely mediate these effects. Collectively, ZQC improves glucose and lipid metabolism in T2DM with MASLD by modulating gut microbiota, moderately regulating PPARγ signaling, and enhancing β-cell function, providing mechanistic insight into its therapeutic potential.</p>

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

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