The emerging contaminant HFPO-TA impairs hepatic glucose metabolism and induces pparγ-associated lipid metabolic disorders in zebrafish

Hexafluoropropylene oxide trimer acid (HFPO-TA) is a new alternative to PFOA; it is already widely used and has caused global pollution. Previous studies have suggested that HFPO-TA may influence hepatic glucose and lipid metabolism via PPAR signaling pathway, however, the underlying molecular mechanism remains unclear. Here, a model of pparγ-knockout (pparγ-KO) zebrafish was used to investigate the mechanisms involving the disorders of glucose and lipid metabolism in the liver induced by HFPO-TA. In this study, a range of techniques were employed, including pparγ-KO (pparγ-/-) zebrafish, transgenic zebrafish, histological staining, biochemical assays, fluorescence quantitative PCR, and transcriptomics. Zebrafish were exposed to HFPO-TA at concentrations of 1.25, 5 and 20 μM for 72 h post-exposure (hpe). The results indicated that exposure to HFPO-TA induced hepatomegaly, neutrophilic infiltration and hepatic lipid accumulation, accompanied by significantly elevated total cholesterol (TC) and triglyceride (TG) levels. In addition, exposure to HFPO-TA was associated with reduced glucose uptake and hepatic glycogen synthesis (as evidenced by downregulated expression of gys2). Using pparγ-KO zebrafish, we found that pparγ knockout attenuated HFPO-TA-induced lipid accumulation and reduced TC and TG elevations, but further exacerbated the inhibition of glucose uptake and glycogen synthesis. pparγ activation was associated with lipid metabolism disorders in the livers of zebrafish, correlating with increased lipid accumulation and liver damage. Collectively, these results reveal that HFPO-TA activates pparγ signaling to induce lipid metabolic disorders, providing important insights for risk assessment of metabolic diseases associated with environmental pollutants.