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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, ?-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.

SUBMITTER: Lin W

PROVIDER: S-EPMC5451243 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Lin Wen W Vann David R DR Doulias Paschalis-Thomas PT Wang Tao T Landesberg Gavin G Li Xueli X Ricciotti Emanuela E Scalia Rosario R He Miao M Hand Nicholas J NJ Rader Daniel J DJ

The Journal of clinical investigation 20170508 6

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 dec ...[more]

PMID: 28481222

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Project description:Abstract Objectives The SLC39A8 gene encodes a divalent metal transporter, ZIP8. ZIP8 polymorphisms are associated with pleiotropic effects including altered risks for schizophrenia. Our objective is to determine the different brain MRI phenotypes associated at or near the SLC39A8 (ZIP8) genetic locus using a phenome-wide association (PheWAS) approach followed by joint and conditional association analysis. Methods Using the summary statistics database containing brain MRI genome-wide association study (GWAS) data, we systematically selected all brain MRI phenotypes which were associated with single-nucleotide polymorphisms (SNPs) within 1 million bp of the SLC39A8 genetic locus, as defined as reaching a P-value significance cutoff of P < 5.0 × 10–8. For all brain MRI phenotypes reaching significance, we used GCTA-COJO to determine the number of independent association signals using settings of P < 1.0 × 10–5 and a window of 10 million base pairs. Using SNPclip and the European 1000 Genomes linkage panel with a linkage disequilibrium cutoff of r2 > 0.8, we identified SNP candidates at each index SNP. Linkage equilibrium for brain phenotypes with multiple independent signals was confirmed by LDpair. Results We identified 25 brain MRI phenotypes that vary due to MRI type and brain region that all contain a SNP associated with the SLC39A8 locus. All of these datasets have at least 1 index SNP directly labeling or in high linkage disequilibrium with rs13107325, which encodes a missense mutation in the SLC39A8 (ZIP8). Among the 25 datasets, an additional 4 association signals were identified by GCTA-COJO and confirmed to be in linkage equilibrium with rs13107325 using LDpair. For these additional association signals, probable causative SNPs were identified from the index SNP using SNPclip. Conclusions From the 25 brain MRI phenotypes, we identified new probable causative SNPs in addition to a previously reported missense SNP (rs13107325) associated with schizophrenia. This study provides leads into how SNPs in genes involved in trace metal transport influence brain structures and affect risks for schizophrenia. Funding Sources This work was funded by grants from the Oklahoma Center for the Advancement of Science and Technology and the Oklahoma Agricultural Experiment Station.

Dataset Information

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

Publications

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

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