Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity
Wen Lin, … , Nicholas J. Hand, Daniel J. Rader
Wen Lin, … , Nicholas J. Hand, Daniel J. Rader
Published May 8, 2017
Citation Information: J Clin Invest. 2017;127(6):2407-2417. https://doi.org/10.1172/JCI90896.
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Research Article Genetics Metabolism

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

Abstract

Genetic variants at the solute carrier family 39 member 8 (SLC39A8) gene locus are associated with the regulation of whole-blood manganese (Mn) and multiple physiological traits. SLC39A8 encodes ZIP8, a divalent metal ion transporter best known for zinc transport. Here, we hypothesized that ZIP8 regulates Mn homeostasis and Mn-dependent enzymes to influence metabolism. We generated Slc39a8-inducible global-knockout (ZIP8-iKO) and liver-specific–knockout (ZIP8-LSKO) mice and observed markedly decreased Mn levels in multiple organs and whole blood of both mouse models. By contrast, liver-specific overexpression of human ZIP8 (adeno-associated virus–ZIP8 [AAV-ZIP8]) resulted in increased tissue and whole blood Mn levels. ZIP8 expression was localized to the hepatocyte canalicular membrane, and bile Mn levels were increased in ZIP8-LSKO and decreased in AAV-ZIP8 mice. ZIP8-LSKO mice also displayed decreased liver and kidney activity of the Mn-dependent enzyme arginase. Both ZIP8-iKO and ZIP8-LSKO mice had defective protein N-glycosylation, and humans homozygous for the minor allele at the lead SLC39A8 variant showed hypogalactosylation, consistent with decreased activity of another Mn-dependent enzyme, β-1,4-galactosyltransferase. In summary, hepatic ZIP8 reclaims Mn from bile and regulates whole-body Mn homeostasis, thereby modulating the activity of Mn-dependent enzymes. This work provides a mechanistic basis for the association of SLC39A8 with whole-blood Mn, potentially linking SLC39A8 variants with other physiological traits.

Authors

Wen Lin, David R. Vann, Paschalis-Thomas Doulias, Tao Wang, Gavin Landesberg, Xueli Li, Emanuela Ricciotti, Rosario Scalia, Miao He, Nicholas J. Hand, Daniel J. Rader

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Figure 3

ZIP8 reclaims Mn from the bile.

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ZIP8 reclaims Mn from the bile. (A and B) Immunofluorescence analysis of...
(A and B) Immunofluorescence analysis of ZIP8 (green) and MDR1 (magenta) localization in Slc39a8fl/fl and ZIP8-LSKO mouse liver sections. Arrows indicate bile ducts. Results are representative of 3 independent experiments. (C) 54Mn uptake study of HEK293T cells overexpressing human ZIP8 (n = 3). (D) ICP-MS analysis of Mn levels in the bile of 12- to 14-week-old male Slc39a8fl/fl and ZIP8-LSKO mice (n = 4). (E) ICP-MS analysis of Mn levels in the bile of male B6 mice injected with AAV-null or AAV-ZIP8 at 10 weeks of age and sacrificed 4 weeks after injection (n = 6 and 5, respectively). Scale bars: 10 μm. All data are shown as the mean ± SD. ***P ≤ 0.001, **P ≤ 0.01, and *P ≤0.05, by Student’s t test.