ArticleThe Journal of clinical investigation2017
Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers, 1 of them a synthesis that pooled it.
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Who cites it
102 citing papers in PubMed, 1 synthesis or guideline pooled it, 167 citations in OpenAlex.
- Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).International journal of molecular sciences · 2022Pooled it
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Manganese availability determines insulin sensitivity by enhancing Akt activity.bioRxiv : the preprint server for biology · 2026Article
- Article
- Manganese: biology, physiology and role in disease.Cell discovery · 2026Review
- Overlaps in mammalian iron and manganese homeostasis: recent advances.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- Junctions, Transporters, and Interactions of Endothelial Cells: Regulation by Ethanol.International journal of molecular sciences · 2026Review
- Allosteric modulation of the solute carrier transporter SLC39A8 potentiates manganese and cadmium uptake.The Journal of clinical investigation · 2025Article
- Removal of Toxic Metabolites-Chelation: Manganese Disorders.Journal of inherited metabolic disease · 2025Review
- SLC39A8-mediated zinc dyshomeostasis potentiates kidney disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Effects of Mn Deficiency on Hepatic Oxidative Stress, Lipid Metabolism, Inflammatory Response, and Transcriptomic Profile in Mice.Nutrients · 2025Article
- Metal Transporter GeneNutrients · 2025Article
- An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.iScience · 2025Article
- Systematic analysis of naturally occurring missense mutations in human manganese transporters: prediction and structural insights.bioRxiv : the preprint server for biology · 2025Article
- Manganese Neurotoxicity and Familial Disorders of Manganese Transport.Annals of the Child Neurology Society · 2025Review
- Article
- ZIP8 Regulates Inflammation and Macrophage Polarisation in Intervertebral Disc Degeneration via the Wnt/β-Catenin Pathway.Journal of cellular and molecular medicine · 2025Article
- Plasma GlycA, a Glycoprotein Marker of Chronic Inflammation, and All-Cause Mortality in Cirrhotic Patients and Liver Transplant Recipients.International journal of molecular sciences · 2025Observational
- Gut to brain: essential micronutrient and trace element manganese transport, function and toxicity.Frontiers in physiology · 2025Review
42 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.