Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2+

Abstract

The blood triacylglycerol level is one of the main determinants of blood Mg 2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg 2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg 2+ concentrations. Using samples from 285 overweight individuals (BMI >27 kg/m 2 ) 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 2+ 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 2+ , triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg 2+ -containing solutions to study the direct interaction between Mg 2+ and NEFAs. In the cohort of overweight individuals, serum Mg 2+ 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 2+ concentration both in mice (Δ plasma Mg 2+ −0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg 2+ −0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg 2+ may be explained by direct binding of Mg 2+ to NEFAs. Moreover, Mg 2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg 2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg 2+ 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 2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg 2+ concentration, and therefore, our data challenge how the fractional excretion of Mg 2+ is calculated and interpreted in the clinic.