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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014638-09
Application #
8593293
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Lawler, Cindy P
Project Start
2006-09-01
Project End
2017-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
9
Fiscal Year
2014
Total Cost
$407,007
Indirect Cost
$154,990
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Kim, Jonghan; Wessling-Resnick, Marianne (2014) Iron and mechanisms of emotional behavior. J Nutr Biochem 25:1101-7
Kim, Jonghan; Jia, Xuming; Buckett, Peter D et al. (2013) Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia. FASEB J 27:1657-63
Seo, Young Ah; Li, Yuan; Wessling-Resnick, Marianne (2013) Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. Neurotoxicology 38:67-73
Byrne, Shaina L; Krishnamurthy, Divya; Wessling-Resnick, Marianne (2013) Pharmacology of iron transport. Annu Rev Pharmacol Toxicol 53:17-36
Kim, Jonghan; Li, Yuan; Buckett, Peter D et al. (2012) Iron-responsive olfactory uptake of manganese improves motor function deficits associated with iron deficiency. PLoS One 7:e33533
Ruvin Kumara, V M; Wessling-Resnick, Marianne (2012) Olfactory ferric and ferrous iron absorption in iron-deficient rats. Am J Physiol Lung Cell Mol Physiol 302:L1280-6
Johnson, Erin E; Wessling-Resnick, Marianne (2012) Iron metabolism and the innate immune response to infection. Microbes Infect 14:207-16
Li, Yuan; Kim, Jonghan; Buckett, Peter D et al. (2011) Severe postnatal iron deficiency alters emotional behavior and dopamine levels in the prefrontal cortex of young male rats. J Nutr 141:2133-8
Burpee, Tyler; Mitchell, Paul; Fishman, Douglas et al. (2011) Intestinal ferroportin expression in pediatric Crohn's disease. Inflamm Bowel Dis 17:524-31

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