Exploring the Mechanisms by which Increasing Dietary Protein Induces Iron Transporter Expression and Improves Intestinal Iron Absorption

Iron deficiency is the most common nutritional deficiency worldwide. Whole body iron balance is primarily controlled through the regulation of intestinal iron absorption. Therefore, the identification of factors that affect iron absorption is important for the development of therapies aimed at improving iron status in deficient individuals. We recently found that increasing dietary protein in rats enhances duodenal iron absorption. This protein-induced increase in iron absorption is associated with augmented transcript levels of key intestinal iron transporters, including the iron importer, DMT1. To determine whether dietary protein directly affects DMT1 expression in vitro, the effect of amino acid supplementation on DMT1 transcript expression and promoter activity was evaluated in Caco-2 cells. Amino acids significantly augmented DMT1 transcript expression by 1.8-fold (P = 0.004) and DMT1 promoter activity by 1.6-fold (P \u3c 0.0001) compared to control cells. Since hepcidin is a major regulator of iron absorption and iron transporter expression, the impact of increasing dietary protein/amino acids on hepatic hepcidin expression was evaluated in vivo in rats and in vitro in primary rat hepatocytes. In rats consuming a high protein diet, hepatic hepcidin expression was suppressed by 44% compared to those on a medium protein diet (P = 0.0006). There was no direct effect of amino acids on hepcidin transcript expression in primary hepatocytes. Finally, to determine whether the effect of dietary protein on iron absorption is relevant to humans, iron status of postmenopausal women who recently completed a double-blind placebo controlled dietary protein supplementation trial was examined. Acutely increasing dietary protein had no significant effect on serum iron status parameters including serum ferritin, hepcidin, and % transferrin saturation. In conclusion, increasing dietary protein in the short-term in rats significantly enhances intestinal iron absorption, which is due at least in part to enhanced duodenal DMT1 transcription and reduced hepatic hepcidin expression. However, acutely increasing protein intake has no significant impact on iron status in iron-replete postmenopausal women. Future work is needed to determine the mechanisms by which increasing dietary protein/amino acids affect duodenal DMT1 transcription and hepatic hepcidin expression and its relevance to the treatment of iron deficiency in humans