The liver is the organ that responds to nutritional disturbances including
magnesium deficiency. The present study evaluated cellular responses to
magnesium deficiency using model cells of the liver, namely, HepG2 cells as hepatocytes, RAW264.7 cells as Kupffer cells and human umbilical vein endothelial cells (HUVECs) as vascular endothelial cells; we examined effects of culture with
magnesium deficient medium on cell responses in individual types of cells as well as interactive responses among cells. Metabolomic analyses indicated that
magnesium deficiency differentially affected the cellular content of metabolites among HepG2 cells, RAW264.7 cells and HUVECs. The cellular content of the metabolites in HepG2 cells and HUVECs was also affected by the
conditioned medium from RAW264.7 cells cultured with the
magnesium-deficient media. The changes in HUVECs partly resembled those of the livers of
magnesium-deficient rats previously described.
RNA-seq analyses indicated that
magnesium deficiency modulated the expression levels of molecules related to the
ubiquitin-
proteasome pathway and oxidative stress/
antioxidant response in HepG2 cells and RAW264.7 cells, respectively. Furthermore, when HUVECs were co-cultured with RAW264.7 cells,
lipopolysaccharide-induced expression of
interleukin (IL)-1β and
IL-6 was enhanced by
magnesium deficiency, depending on the presence of RAW264.7 cells. The present study reveals that
magnesium deficiency affects cellular metabolism in HepG2 liver cells, RAW264.7 macrophages and HUVECs, and that the modulation of cellular responses to extracellular
magnesium deficiency in HUVECs depends on the presence of RAW264.7 cells. The complex responses in individual cells and through cell interactions partly explain the regulatory reaction to
magnesium deficiency in the liver.