SLC39A8/ZIP8 Influences Complex Traits by Regulating Metal Ion Metabolism

Common genetic variants at the SLC39A8 locus are genome-wide significantly associated with a variety of traits in human, and SLC39A8 loss-of-function results in developmental defects in multiple organs of both human and mice. SLC39A8 encodes ZIP8, a metal ion transporter best known for transporting manganese (Mn) and zinc (Zn), two essential nutrients required for general metabolism. The goal of my dissertation is to explore the mechanism in which SLC39A8 mediates metal ion transport in vivo and to test the hypothesis that SLC39A8 pleiotropically influences complex traits by regulating metal ion transport. I took advantage of novel Slc398a8 mouse models, cell lines, and samples from human carriers of an SLC39A8 variant. I discovered that hepatic Zip8 reclaims Mn from biliary excretion to maintain whole-body Mn homeostasis, and that hepatic Zip8 is a quantitative regulator of whole-body Mn. Slc398a88 deletion in mice leads to protein N-glycosylation defects indicative of decreased activity of a Mn-dependent enzyme, β-1, 4-galactosyltransferase, while homozygosity of a SLC39A8 loss-of-function variant is associated with hypogalactosylation, suggesting that protein N-glycosylation may be related to the association of SLC39A8 with complex traits in GWAS. Slc398a88 acts through Mn to quantitatively modulate the activity of arginase, another Mn-dependent enzyme that influences blood pressure via nitric oxide (NO). Slc398a88 deletion in mice results in increased NO production, decreased blood pressure, and protection against high-salt-induced hypertension, while homozygosity of the SLC39A8 loss-of-function variant in human is associated with increased NO, providing a plausible explanation for the association of SLC39A8 with blood pressure. Slc398a88 deletion in combination with a Zn deficient diet decrease HDL-C in the blood, suggesting Zn may be involved in the association of SLC39A8 with HDL-C. During embryonic development, Slc398a88 deletion in mice recapitulates hallmarks of left ventricular noncompaction, a rare cardiomyopathy in human. Mechanistically, Slc398a88 deletion decreases cellular Zn uptake, which leads to reduced metal-regulatory transcription factor 1 transcriptional activity, decreased Adamts metalloproteinase transcription, and impaired extracellular matrix degradation that has been implicated in noncompaction. Thus my dissertation reveals the mechanism in which Slc398a88 mediates Mn transport in vivo and demonstrates that Slc398a88 acts through Mn and Zn to modulate the activity of Mn and Zn-dependent enzymes and transcription factors, which in turn pleiotropically influence complex traits especially blood pressure and heart ventricle development