While studying Mg²⁺ transport in liver cells, we have observed a close association between Mg²⁺ extrusion and glucose output in liver cells. The hormones responsible for Mg²⁺ extrusion (catecholamine, glucagon, etc.) are the same hormones released by our body to maintain glucose homeostasis. The same is true for Mg²⁺ accumulation, as insulin promotes both glucose and Mg²⁺ accumulation within the liver.

We also observed that reducing dietary Mg²⁺ content or extracellular Mg²⁺ concentration in culture media resulted in a decreased accumulation and utilization of glucose within the hepatocyte. At the same time, PPARg and SREBP1c, two key regulators of fatty acid oxidation and metabolism were upregulated. These changes in liver metabolism are of major importance if we consider the current incidence of obesity in the US and the fact that the current Western diet provides about 35-40% less Mg²⁺ than physiologically required.

At the cellular level, Mg²⁺ deficiency has two distinct effects:

1. At the mitochondrial level, the decrease in Mg²⁺ content affect the pyruvate dehydrogenase (PDH activity). This enzyme is active in the dephosphorylate state, and the PDH-phosphatase is Mg²⁺-dependent. Our studies indicate that the phosphatase is significantly less active in low Mg²⁺, resulting in a decreased enzymatic activity of the PDH, a decreased production of Acyl-CoA required for an efficient Krebs cycle activity, and ultimately a decreased ATP production.
2. A decrease in cytoplasmic Mg²⁺ upregulated the transport of glucose 6-phosphate into the endoplasmic reticulum, resulting in an increased hydrolysis via glucose 6-phosphatase and an increased conversion to 6 phosphoglucono-lactone by the glucose 6-phosphate dehydrogenase (G6PD). This second metabolic conversion represents the rate limiting step for the activation of the pentose shunt for energetic purposes within the hepatocyte. More importantly, the G6PD activity is associated with the production of intrareticular NADPH that is oxidized during the conversion of cortisone to cortisol by the 11-b-OH-steroid dehydrogenase-1. Indeed, Mg²⁺ deficient liver cells produce 2-4 times more cortisol, which can in turn affect the responsiveness of the hepatocyte to insulin (insulin resistance). These studies are of relevance for pathological conditions characterized by an increased presence of fatty acid within the liver such as it is observed under alcoholism and ASH (alcoholic steatohepatitis), obesity and NASH (non-alcoholic steatohepatitis), and diabetes type II.

Exposure to low extracellular Mg²⁺ reduces the cell reduplication rate. This has been observed in hepatocytes in culture and also in fibroblasts and cardiac myocytes. It is presently under investigation whether the slow-down in cell reduplication rate is the result of the energetic deficit described previously or whether magnesium deficiency affect the operation of specific genes and kinases (e.g. p21, p27 and p53) involved in the process.

These studies are of relevance to understand the role of magnesium in hepatocyte reduplication rate under physiological conditions as well as under pathological conditions such as alcoholism, hepatitis, cirrhosis, in which a high rate of hepatocyte cell death is observed. These studies may also lead to better understand unregulated cell growth (i.e. hepatic tumor and cancer)

Magnesium sulfate (MgSO₄) is the therapy of choice for pathological conditions such as eclampsia (convulsion and hypertension during gestation) and pre-term labor. The effectiveness of MgSO4 has been attributed to its ability to inhibit Ca²⁺ entry through L-type Ca2+ channels in neurons and vascular endothelial cells (in eclampsia) and myometrium cells in pre-term labor. While there is merit in these assumptions, recent studies conducted in conjunction with Dr. Bernstein, an OB/GY physician at UH have evidence that MgSO4 greatly reduces synthesis and production of pro-inflammatory cytokine by inhibiting NF-kB signaling in monocytes of women undergoing pre-term labor. Importantly, pre-term newborns present a high incidence of cerebral palsy, which has been attributed to higher than normal levels of pro-inflammatory cytokines in the cerebral fluid.

We are continuing our studies with Dr. Bernstein to understand the short-and long-term implications of changes in cellular Mg²⁺ for the systemic response of immune-competent cells such as lymphocytes and dendritic cells. We are also expanding our study to the Kupffer cells, as these liver resident macrophages are involved in mediating the immune and inflammatory response in livers of animals and humans exposed to alcohol (ASH) and hepatitis.