- For general background in zinc homeostasis and ZIP protein function please refer to “The Role of the Slc39a Family of Zinc Transporters in Zinc Homeostasis in Skin”
Due to the crucial role that zinc plays in a wide range of proteins, zinc homeostasis is paramount to the health and functionality of a system. Zinc homeostasis is mainly coordinated by two families of proteins, ZIP importers and ZnT efflux transporters. Lost in function in these proteins will coincide with either zinc deficiency or toxicity, which will damage the viability of the cell or tissue. ZIP4 is an importer protein that is enriched in keratocytes and is the main coordinator of keratinocyte proliferation and differentiation.
Non-functional or misregulated ZIP4 will result in the manifestation of the rare autosomal recessive genetic disorder Acrodermatitis Entropatica (AE), a disease whose hallmark characteristics are skin lesions, diarrhea, and nail dystrophy due to an extreme zinc deficiency. AE can be caused to structural mutations which shut down ZIP4 or malfunctions in the regulatory pathway that lead to an underexpression of the protein.
It is known that the overexpression of ZIP4 will cause an increase in cellular zinc levels, so a group of researchers from Japan looked into methods to increase the expression of ZIP4. ZIP4 is a membrane protein that is located on the plasma membrane when intercellular zinc levels are low and then endocytosed when zinc levels are high. Using different tissue cultures comprised of different cells-which utilize the same dynamic modulation of ZIP4 expression-the researchers screened extracts from many common foods to see their impact on ZIP4 expression. Two soybean extracts were found to increase the expression of ZIP4, Soyaflavon HG (SHG) and Soyhealth SA (SSA). The two extracts enriched the presence of ZIP4 Hepa cells (which utilize the same dynamic regulation of ZIP4) generally and also increased expression of the protein on the apical membrane of Caco2 cells (which mimic the morphology of small intestinal cells). Furthermore, it was found that the extracts also mitigated the endocytosis and degradation of the protein, effectively limiting the loss of concentration of ZIP4.
While the extracts did result in an increase in ZIP4 expression, they did not change the functionality of the protein itself. If the ZIP4 gene is affected by the mutations that cause AE, the soybean extracts will increase the accumulation of the mutant protein at the apical membrane but there will not be a rescue of function. So the application of a treatment utilizing these extracts would not improve patients whose AE is the result of a loss-of-function mutation, but it could rescue the function of an AE patient whose ZIP4 regulatory pathway is misfunctioning.
Sources:
Bin, B. H., Hojyo, S., Seo, J., Hara, T., Takagishi, T., Mishima, K., & Fukada, T. (2018). The Role of the Slc39a Family of Zinc Transporters in Zinc Homeostasis in Skin. Nutrients, 10(2), 219. https://doi.org/10.3390/nu10020219
Hashimoto, A., Ohkura, K., Takahashi, M., Kizu, K., Narita, H., Enomoto, S., Miyamae, Y., Masuda, S., Nagao, M., Irie, K., Ohigashi, H., Andrews, G. K., & Kambe, T. (2015). Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting. The Biochemical journal, 472(2), 183–193. https://doi.org/10.1042/BJ20150862