Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function.
The trace element copper (Cu) is a cofactor for biochemical functions ranging from energy generation to iron (Fe) acquisition, angiogenesis, and free radical detoxification. While Cu is essential for life, the molecules that mediate dietary Cu uptake have not been identified. Ctr1 is a homotrimeric protein, conserved from yeast to humans, that transports Cu across the plasma membrane with high affinity and specificity. Here we describe the generation of intestinal epithelial cell-specific Ctr1 knockout mice. These mice exhibit striking neonatal defects in Cu accumulation in peripheral tissues, hepatic Fe overload, cardiac hypertrophy, and severe growth and viability defects. Consistent with an intestinal Cu absorption block, the growth and viability defects can be partially rescued by a single postnatal Cu administration, indicative of a critical neonatal metabolic requirement for Cu that is provided by intestinal Ctr1. These studies identify Ctr1 as the major factor driving intestinal Cu absorption in mammals.
Nose
Yasuhiro
Y
Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kim
Byung-Eun
BE
Thiele
Dennis J
DJ
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003300:Copper / Q000172:deficiency* / Q000494:pharmacology; D000079923:Copper Transporter 1; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007408:Intestinal Absorption / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000503:physiopathology; D007422:Intestines / Q000503:physiopathology; D007501:Iron / Q000378:metabolism*; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D026901:Membrane Transport Proteins; C510533:Slc31a1 protein, rat; D003300:Copper; D007501:Iron