Insulin deficiency alters cellular cholesterol metabolism in murine macrophages

Abstract

Mice made insulin deficient by the injection of streptozocin develop hyperglycemia and hypertriglyceridemia with triglyceride-rich, very-low-density lipoproteins (VLDLs). Thioglycolate-elicited peritoneal macrophages freshly isolated from insulin-deficient mice have increased activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is reflected in a greater rate of cholesterol synthesis by these macrophages. In contrast, thioglycolate-elicited macrophages from control mice with diet-induced hypertriglyceridemia had normal levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cell surface receptors responsible for VLDL uptake are decreased in macrophages isolated from insulin-deficient mice, although receptors for acetylated low-density lipoproteins are not altered. Insulin treatment of insulin-deficient mice lowers plasma glucose and triglyceride concentrations. Additionally, insulin treatment returns the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase and the rate of cholesterol synthesis in thioglycolate-elicited macrophages to normal while increasing the number of receptors responsible for VLDL uptake. It is suggested that the increases in 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and the rate of cholesterol synthesis in macrophages isolated from insulin-deficient mice are secondary to the reduction in the number of receptors responsible for VLDL uptake induced by insulin deficiency. These alterations in the cholesterol metabolism of macrophages occurring with insulin deficiency may have important implications for the atherosclerotic process in diabetes mellitus.