Depalmitoylation of TEAD1 facilitates lipid droplet accumulation and resistance to oxidative stress by transactivating PP2Acα

Abstract

Background

An overdose of acetaminophen (APAP) triggers acute liver failure via excessive production of reactive oxygen species (ROS). Modulating lipid droplet (LD) homeostasis in hepatocytes can protect against hepatic oxidative stress. However, rapid accumulation of LDs in the liver shortly after APAP administration remains unclear.

Methods

KEGG analysis was conducted to investigate the pathways associated with APAP-induced acute liver failure using data from the GSE database. Lipid metabolism-related pathways and the Hippo signaling pathway were identified as the most significantly enriched pathways. To investigate the functional role of Hippo signal in hepatotoxicity, hepatocyte-specific TEAD1 knockout mice were generated and challenged with APAP.

Results

Compared to wild-type controls, TEAD1-KO mice demonstrated significantly exacerbated hepatotoxicity, accompanied by reduced hepatic triglyceride (TG) content. Conversely, the hepatic overexpression of TEAD1 elevated TG levels and ameliorated APAP-induced liver injury. ChIP assays demonstrated that TEAD1 binds directly to the promoter region of PP2Acα, transcriptionally regulating its expression and promoting ACC1 dephosphorylation, thereby enhancing de novo lipogenesis. Furthermore, depalmitoylation of TEAD1 increased its capacity to form transcriptional condensates at the PP2Acα locus, resulting in enhanced PP2Acα transcriptional activity. This molecular mechanism facilitated the formation of numerous enlarged LDs, which conferred hepatoprotective effects against APAP toxicity.

Conclusion

Decreased palmitoylation of TEAD1 during the early stages of APAP administration facilitates rapid de novo lipid synthesis in response to lipid peroxidation. This process occurs through the enhanced capacity of TEAD1 for liquid-liquid phase separation (LLPS), which subsequently initiates transcription of the PP2Acα gene.