Glibenclamide inhibits accumulation of cholesteryl ester in THP-1 human macrophages.

Abstract

Glibenclamide is an adenosine triphosphate (ATP)-sensitive potassium channel inhibitor that is widely used in treating diabetes mellitus. However, the effects of this drug on cholesterol metabolism and atherogenesis are not well known. We investigated the effects of this agent on the cellular cholesterol metabolism in cultured human macrophages. The effect of glibenclamide was evaluated by the measurement of the cellular contents of total cholesterol, free cholesterol, and cholesteryl ester in the presence of low-density lipoprotein (LDL). The effect on the degradation and association of 125I-labeled LDL (125I-LDL) also were determined. Cholesterol efflux was measured in the absence and the presence of high-density lipoprotein (HDL). The secretion of apolipoprotein E also was determined. The synthesis and hydrolysis of cholesteryl ester were evaluated. Glibenclamide stimulated both synthesis and hydrolysis of cholesteryl ester, and inhibited the net accumulation of cholesteryl ester by LDL in a concentration-dependent manner and even decreased its content compared with time 0 control. This drug had no effect on the degradation or association of 125I-LDL. Glibenclamide promoted the HDL-independent cholesterol efflux by decreasing esterified cholesterol and increasing the release of free cholesterol and secretion of apolipoprotein E into the medium. The other potassium channel inhibitors or openers had no effect on the cellular cholesterol levels. These results suggest that glibenclamide inhibits the accumulation of cholesteryl ester in macrophages by enhancing the hydrolysis of cholesteryl ester as well as by increasing cholesterol efflux, and possibly, by increasing the secretion of apolipoprotein E. These effects appeared to be unrelated to an effect on the potassium channel. Inhibition of accumulation of cellular cholesterol by glibenclamide might be favorable for the prevention of atherosclerotic disease.