Activating transcription factor 4 mediates rare sugar-induced transactivation of the fibroblast growth factor 21 promoter

Sugar intake induces the secretion of fibroblast growth factor 21 (FGF21) from the liver. Subsequently, FGF21 acts on the hypothalamus to reduce sugar intake. As simple sugars are obesogenic, low-calorie rare sugars can be used as alternatives. Accordingly, d-allulose, d-tagatose, and d-sorbitol induce Fgf21 expression in primary mouse hepatocytes. Carbohydrate-responsive element-binding protein regulates simple sugar-induced FGF21 expression. Therefore, this study aimed to determine whether the same mechanism was responsible for rare sugar-induced FGF21 expression. Promoter analysis, knockdown assays, and chromatin immunoprecipitation were performed using primary mouse hepatocytes. Our findings demonstrate that these three rare sugars transactivate the mouse Fgf21 promoter by inducing activating transcription factor 4 (ATF4), which binds to an amino acid response element located 1027 base pairs upstream of the transcription start site. These results suggested a novel mechanism for sugar-induced FGF21 expression.