We advance the hypothesis that hepcidin regulates manganese metabolism. Accumulating evidence from in vitro studies suggests that ferroportin, the target of hepcidin regulation, plays a role in the transport of manganese. Our in vivo studies of Hfe-/- mice strongly support this idea. We will directly test its function in manganese metabolism using flatiron (ffe+/-) mice as a genetic model of ferroportin deficiency. While ferroportin function in iron export by intestinal enterocytes and macrophages of the reticuloendothelial system has been established, its activity has yet-to-be fully explored in hepatocytes where the exporter also is highly expressed. We hypothesize that in the liver, ferroportin functions in biliary excretion of manganese, a known homeostatic pathway that clears excess metal from the body. Based on our model, we speculate that circulating manganese levels are suppressed during inflammation by hepcidin, an idea that is well-supported by known host-pathogen interactions. Finally, we will determine the mechanism responsible for increased olfactory manganese absorption we have observed in Hfe knockout mice. The original new ideas forming the basis of our research will have a powerful sustaining influence on the field of metal metabolism by creating new paradigms to explain the molecular basis for manganese homeostasis.

Public Health Relevance

Manganese is both an essential nutrient and a potent toxicant. Manganese homeostasis guards against the neurotoxic effects of excess metal while providing a sufficient source for growth and development. There is growing appreciation that airborne manganese is effectively taken up across the air-blood and air-brain barriers to cause neurological damage. Our studies will define the molecular factors involved in this process and build a greater understanding of the health risks involved.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Lawler, Cindy P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Public Health
United States
Zip Code
Rodan, Lance H; Hauptman, Marissa; D'Gama, Alissa M et al. (2018) Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies. Mol Genet Metab 124:161-167
Thompson, Khristy J; Hein, Jennifer; Baez, Andrew et al. (2018) Manganese transport and toxicity in polarized WIF-B hepatocytes. Am J Physiol Gastrointest Liver Physiol 315:G351-G363
Seo, Young Ah; Elkhader, Jamal A; Wessling-Resnick, Marianne (2016) Distribution of manganese and other biometals in flatiron mice. Biometals 29:147-55
Seo, Young Ah; Wessling-Resnick, Marianne (2015) Ferroportin deficiency impairs manganese metabolism in flatiron mice. FASEB J 29:2726-33
Wessling-Resnick, Marianne (2015) Nramp1 and Other Transporters Involved in Metal Withholding during Infection. J Biol Chem 290:18984-90
Kim, Jonghan; Wessling-Resnick, Marianne (2014) Iron and mechanisms of emotional behavior. J Nutr Biochem 25:1101-1107
Veuthey, Tania; Hoffmann, Dana; Vaidya, Vishal S et al. (2014) Impaired renal function and development in Belgrade rats. Am J Physiol Renal Physiol 306:F333-43
Seo, Young Ah; Li, Yuan; Wessling-Resnick, Marianne (2013) Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. Neurotoxicology 38:67-73
Kim, Jonghan; Buckett, Peter D; Wessling-Resnick, Marianne (2013) Absorption of manganese and iron in a mouse model of hemochromatosis. PLoS One 8:e64944
Kim, Jonghan; Jia, Xuming; Buckett, Peter D et al. (2013) Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia. FASEB J 27:1657-63

Showing the most recent 10 out of 31 publications