Co-Exposure to Different Zinc Concentrations and High-Fat Diet Modules Endoplasmic Reticulum Stress and Lipotoxicity through the MTF-1/GPx7 Axis in Yellow Catfish (<i>Pelteobagrus fulvidraco</i>)

As industrialization and societal development accelerate, various organisms, including humans, are exposed to environmental hazards, such as zinc (Zn) and high-fat diet (HFD). These widespread exposures pose significant threats to public health; however, the combined effects and underlying mechanisms of these environmental factors on lipotoxicity remain unclear. In this study, the yellow catfish (<i>Pelteobagrus fulvidraco</i>) was used as a model to investigate the impact of different Zn levels and HFD coexposure on hepatic lipotoxicity. The results indicated that low concentrations of Zn (L-Zn) significantly reduced hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum (ER) stress compared to HFD-only treatment, while high concentrations of Zn (H-Zn) exacerbated these effects. Mechanistically, L-Zn alleviated ER stress by scavenging H₂O₂ and O₂^•- within the ER via the MTF-1/GPx7 pathway. Glutathione peroxidase 7 (GPx7), an ER-resident antioxidant enzyme, played a crucial role in mitigating ER stress and lipotoxicity, with metal-responsive transcription factor 1 (MTF-1) identified as its regulator. This study is the first to demonstrate the dual role of Zn in hepatic lipotoxicity, revealing the Zn²⁺/MTF-1/GPx7 axis as a key modulator of ER stress and lipid metabolism. These findings highlight the importance of considering combined environmental exposures in public health and environmental risk assessments.