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 5

Slc39a8 loss of function results in protein N-glycosylation defects.

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Slc39a8 loss of function results in protein N-glycosylation defects. (A...
(A and B) MALDI-TOF analysis of the N-glycan profile for serum obtained 5 weeks after male Slc39a8fl/fl and ZIP8-iKO mice were injected with tamoxifen at 8 weeks of age. (C and D) MALDI-TOF analysis of the N-glycan profile for serum obtained from 10- to 12-week-old male Slc39a8fl/fl and ZIP8-LSKO mice. Each sample was pooled from 5 mice of the same genotype. White diamonds, sialic acid; yellow circles, galactose; blue squares, N-acetyl-glucosamine; green circles, mannose. The numbers above the peaks indicate the mass-to-charge ratios of the N-glycan species. 2853, disialo-biantennary glycans; 2448, monosialo-digalacto-biantennary glycans; 2257, monosialo-monogalacto-biantennary glycans; 1852, asialo-monogalacto-biantennary glycans; 1661, asialo-agalacto-biantennary glycans; 1416, asialo-agalacto-mono-GlcNAc-biantennary N-glycan. (E) Abundance of monosialo-monogalacto-biantennary glycans in the plasma of rs13107325 major and minor allele homozygotes. N = 11 and 12, respectively. Data are shown as the mean ± SD. Comparisons were performed using Student’s t test. *P ≤ 0.05.