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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 Article has an altmetric score of 2

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

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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 4

ZIP8 acts through Mn to quantitatively modulate arginase activity.

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ZIP8 acts through Mn to quantitatively modulate arginase activity.
(A) A...
(A) Arginase activity in the livers of 8- to 10-week-old male Slc39a8fl/fl mice (WT) injected with AAV-null and ZIP8-LSKO mice injected with AAV-null or AAV-ZIP8 and sacrificed 4 weeks after injection (n = 7, 4, and 4, respectively). (B) Arginase activity in the livers of 10-week-old male B6 mice injected with AAV-null or AAV-ZIP8 and sacrificed 4 weeks after injection (n = 5 and 6, respectively). (C) Western blot analysis of arginase protein in the liver lysates of mice depicted in A and B. (D and E) Arginase activity in the livers of 10-week-old male Slc39a8fl/fl and ZIP8-LSKO mice after preincubation with increasing concentrations of MnCl2. Lysates from 3 mice of the same genotype were pooled, and 3 technical replicates were performed. (F) Arginase activity normalized to the average of the Slc39a8fl/fl liver lysate at each MnCl2 concentration. (G) Arginase activity in the livers of individual 10-week-old male Slc39a8fl/fl and ZIP8-LSKO mice, with or without preincubation with 250 μM MnCl2 (n = 6 and 7, respectively). (H) Correlation analysis of hepatic Mn levels and arginase activity in all 4 mouse models. Mn levels and arginase activity were normalized to the average of the control groups (n = 41). (I). ICP-OES analysis of kidney Mn levels in 10- to 12-week-old male Slc39a8fl/fl and ZIP8-LSKO mice (n = 5). ICP-OES results were normalized to wet tissue weight. Mn levels were normalized to the average of the control group. (J) Arginase activity in the kidneys of mice described in I (n = 5). (K) Correlation analysis of kidney Mn levels and arginase activity in mice depicted in I and J (n = 10). Mn levels and arginase activity were normalized to the average of the control group. All data are shown as the mean ± SD. Comparisons between 2 groups were performed by Student’s t test. Multiple comparisons in A were performed using 1-way ANOVA and Tukey’s multiple comparisons test, and multiple comparisons in G were performed using 2-way ANOVA and Bonferroni’s post-hoc test. ***P ≤ 0.001, **P ≤ 0.01. Correlation analyses were performed using Pearson’s test.

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