The antidiabetic drug metformin decreases cholesterol metabolism in cultured human fibroblasts.

The effect of the hypoglycemic biguanide drug Metformin was investigated after a 72 h pretreatment of human cultured fibroblasts. Metformin induced a moderate increase in low density lipoprotein binding, uptake and internalization (25% increase after treatment with 5 X 10(-4) M of drug). A decrease in sterol, fatty acid and triacyglycerol synthesis from sodium acetate was observed after pretreatment with the drug, with a dose-dependent effect in the range of 5 X 10(-5) to 5 X 10(-4) M (50% reduction of sterol synthesis after treatment with Metformin 5 X 10(-4) M). This effect was also observed in fibroblasts from a patient with homozygous familial hypercholesterolemia. Cholesterol esterification studied by incorporation of radiolabeled oleic acid was reduced by Metformin (40% of control after treatment with Metformin 5 X 10(-4) M) whereas incorporation into triacylglycerols was less impaired. These effects of Metformin on cholesterol metabolism were observed either in the presence or in the absence of low density lipoproteins. Moreover, Metformin also reduced cholesterol esterification in J774 monocyte-macrophage cells. Metformin also induced a decrease of hydroxymethylglutaryl coenzyme A reductase activity in cultured fibroblasts and a reduction of acyl-coenzyme A: cholesterol-O-acyltransferase activity in cultured fibroblasts and J774 cells.