Increased NEFA levels reduce blood Mg 2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg 2

The blood triacylglycerol level is one of the main determinants of blood Mg concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg concentration 27 kg/m ) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg , triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg -containing solutions to study the direct interaction between Mg and NEFAs. In the cohort of overweight individuals, serum Mg levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg concentration both in mice (Δ plasma Mg -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg may be explained by direct binding of Mg to NEFAs. Moreover, Mg was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg concentration was not affected by the presence of physiological concentrations of other cations. This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg concentration, and therefore, our data challenge how the fractional excretion of Mg is calculated and interpreted in the clinic.