Zinc is an essential mineral that plays a vital role in numerous biological processes, from enzyme function and DNA synthesis to immune response and cellular metabolism. It is often taken as a supplement by fitness enthusiasts and biohackers. In this blog post, we will look at the metabolism of zinc in the body and how genetic variations can influence its absorption and utilization.
Zinc absorption
Zinc absorption primarily occurs in the small intestine, mainly in the duodenum and jejunum. The intestinal lining is equipped with specialized proteins that facilitate the transport of zinc from the gut lumen into enterocytes, the absorptive cells of the intestine. These zinc transporters are divided into two main families: ZIP (or solute carrier 39A, SLC39A) transporters, which move zinc into the cytoplasm of cells, and ZnT (Zinc Transporter, or solute carrier 30, SLC30) proteins, which shuttle zinc out of the cytoplasm into various cellular compartments or back into the intestinal lumen.
ZIP transporters
ZIP transporters increase intracellular zinc concentration by importing zinc from the intestinal lumen into enterocytes or from intracellular vesicles into the cytoplasm.
ZnT transporters
On the other hand, ZnT transporters decrease intracellular zinc concentration by exporting zinc out of cells or sequestering it into intracellular compartments like the Golgi apparatus and vesicles. ZnT1, for instance, is responsible for the efflux of zinc from enterocytes into the bloodstream, thus playing a key role in the systemic distribution of absorbed zinc.
Regulation of zinc absorption
When zinc levels are low, the expression of ZIP transporters, especially ZIP4, is upregulated to increase zinc uptake. Conversely, when zinc levels are sufficient or high, the expression of ZnT transporters is increased to prevent excessive accumulation and potential toxicity.
Key genes in zinc metabolism
Ten SLC30A genes (encoding ZnT proteins) and 14 SLC39A genes (encoding ZIP proteins) have been identified in humans.
ZIP genes
ZIP1
One of the first identified ZIP transporters, ZIP1 plays a role in the uptake of zinc from the extracellular space into cells. It is widely expressed in various tissues and is crucial for maintaining cellular zinc levels, particularly under conditions of marginal zinc deficiency.
ZIP4
ZIP4 is a pivotal transporter for dietary zinc absorption in the small intestine. It is highly responsive to zinc status; when dietary zinc is low, ZIP4 expression is significantly upregulated to enhance zinc uptake. Mutations in the ZIP4 gene can lead to severe zinc deficiency disorders such as acrodermatitis enteropathica.
ZIP8
ZIP8 has been implicated in the immune response and the regulation of inflammation, highlighting its broader physiological roles beyond zinc homeostasis.
ZnT genes
ZnT1
ZnT1 is responsible for exporting zinc from cells into the extracellular space. It is ubiquitously expressed and is particularly important in preventing zinc toxicity by regulating cellular zinc efflux. ZnT1 ensures that intracellular zinc levels remain within a safe and functional range.
ZnT2
This transporter is crucial for the transport of zinc into secretory vesicles. It plays a significant role in lactation, as ZnT2-mediated zinc transport into milk is essential for providing adequate zinc to breastfeeding infants. ZnT2 mutations can affect milk zinc levels, impacting infant nutrition.
ZnT3
ZnT3 is primarily expressed in the brain, where it is involved in the transport of zinc into synaptic vesicles. This process is critical for zinc signaling in the central nervous system and plays a role in cognitive function and synaptic plasticity.
Genetic variations in zinc transporters
In the table below, Ref stands for “reference allele”, Alt stands for “alternative allele”, and the last column indicates the effect of this polymorphism on zinc absorption or transporter function (all these polymorphism have been associated with zinc absorption).
| Gene | rsid | Ref | Alt | Effect |
|---|---|---|---|---|
| SLC30A3 | rs11126936 | G | T | Increased |
| SLC39A8 | rs233804 | C | A | Increased |
| SLC39A14 | rs4872479 | G | T | Increased |
| CA3 | rs1532423 | A | G | Increase |
References
- Junko Fujihara et al. Association of SNPs in genes encoding zinc transporters on blood zinc levels in humans.
- Evans et al. Genome-wide association study identifies loci affecting blood copper, selenium and zinc.
- Day et al. Genetic Variations as Modifying Factors to Dietary Zinc Requirements—A Systematic Review