The finding that liver iron levels were unaffected in Dmt1liv/liv mice indicates that hepatocyte DMT1 is dispensable for the overall iron economy of the liver. In addition, the observation that hepatic iron accumulation and deposition of iron in hepatocytes were unaffected in Selleck Dinaciclib double-mutant Hfe−/−;Dmt1liv/liv and Trfhpx/hpx;Dmt1liv/liv mice demonstrates that hepatocyte DMT1 is not required for development of hepatic iron overload characteristic of hemochromatosis or hypotransferrinemia. Furthermore, no alterations were found in levels of plasma iron, total iron-binding capacity, transferrin saturation, or hemoglobin in single- or double-mutant

Dmt1liv/liv mice, suggesting that inactivation of hepatocyte DMT1 does not affect systemic iron metabolism. The first clue that DMT1 was dispensable for hepatic iron accumulation was provided by studies of the Dmt1−/− mouse, which found that Dmt1−/− neonates had 3 times normal liver iron levels.[9] However, this observation was confounded by the fact that the Dmt1−/− mice had severe anemia and prominent extramedullary erythropoiesis in the liver. Hepatic iron accumulation in Dmt1−/− mice was directly investigated by administering a single IP dose of 5 mg of iron dextran.[9] The iron dextran injection resulted in a large

increase in levels of liver iron, in Selleck Ku0059436 hepatocytes as well as macrophages. Although these observations indicated that an IP injection of a pharmacologic dose of iron (in a nonphysiological form) could load iron into the liver in the absence of DMT1, it is unclear how relevant these data are to usual pathways of hepatic iron uptake and accumulation. Therefore, in the present study, we assessed the role of DMT1 in hepatic iron uptake by IV administering physiologic forms of iron—transferrin or ferric citrate as NTBI18—and by using animal models of human disorders of iron overload. Similar to HFE-related hemochromatosis patients, Hfe−/− mice hyperabsorb selleckchem dietary iron

and deposit the excess in hepatocytes, starting with periportal hepatocytes.[3] Here, we observed a similar pattern of iron deposition in the liver of Hfe−/− mice lacking hepatocyte DMT1 (Hfe−/−;Dmt1liv/liv), indicating that DMT1 is dispensable for hepatocyte iron accumulation in this animal model. Also, similar to hemochromatosis patients, Hfe−/− mice have elevated levels of plasma NTBI, even when transferrin is not fully saturated.[12] Most plasma NTBI is rapidly cleared by hepatocytes and is therefore believed to be a significant contributor to hepatic iron deposition.[11, 12] If so, our studies suggest that hepatocyte DMT1 is not required for NTBI uptake because hepatic iron levels were similar in Hfe−/− mice with or without hepatocyte DMT1. The likelihood that hepatocyte DMT1 is dispensable for the hepatic uptake of NTBI is strongly supported by our observation that hepatic iron accumulation and iron deposition in hepatocytes were unaffected in Trfhpx/hpx mice lacking hepatocyte DMT1 (Trfhpx/hpx;Dmt1liv/liv mice).