Low Zinc Ameliorated the Decrease in Intestinal Copper Level Induced by Low Dietary Copper: Involvement of <scp>SUMOylated</scp> ‐Mtf‐1 and Mtf‐1/Atp7a Pathway

Copper (Cu) and zinc (Zn) are essential trace metal elements for vertebrates, and insufficient intake of trace metal elements can have adverse effects on animal health. Studies suggested that the interaction among trace metal elements played a crucial role in this process. Therefore, the current study was conducted to explore whether low Zn alleviated low dietary Cu-induced decrease in intestinal Cu level and identify potential mechanisms via the in vivo animal experiment and in vitro cell culture. The regulatory relationship between metal response element binding transcription factor 1 (Mtf-1) and ATPase Cu transporting alpha (Atp7a) under low Cu and low Zn was elucidated through electrophoretic mobility shift assays and chromatin immunoprecipitation analysis. The SUMOylation modification of Mtf-1 and its effects on atp7a promoter were determined through immunoprecipitation and dual-luciferase reporter assay. Compared with the control, the low dietary Cu group significantly promoted the transcriptional regulation of atp7a promoter by Mtf-1, leading to intestinal Cu metabolism disorders. However, compared with the low dietary Cu group, the low Cu + low Zn group had significantly inhibited the transcriptional regulation of atp7a promoter by Mtf-1 and alleviated intestinal Cu metabolism disorder caused by low Cu. Mechanistically, Mtf-1 was modified by SUMOylation, and Sumo1-overexpression significantly reduced atp7a promoter activity. Taken together, dietary low Zn alleviated low Cu-induced decrease in intestinal Cu level through the SUMOylated-Mtf-1 and the Mtf-1/Atp7a axis.