Influence of insulin on cholesterol removal from macrophages and cholesterol ester uptake by HepG2 cells

Abstract

The fact that an increased blood insulin level is observed in patients with coronary artery disease (CAD) confirms the hypothesis that insulin promotes the development of atherosclerosis. The low high-density lipoprotein (HDL) concentration observed in such patients may contribute to alteration in reverse cholesterol transport and promote the accumulation of sterols in vascular tissue. We examined the effect of insulin (20-1000 microU mL-1) on cholesterol efflux into HDL3 particles from human blood monocyte/macrophages and rat peritoneal macrophages preloaded with labelled cholesterol esters, and the influence of insulin on the accumulation of sterols by rat liver cells and HepG2 cell line in vitro models. Insulin at concentrations up to 250 microU mL-1 inhibited the efflux of cholesterol from rat macrophages and promoted high uptake of sterols by both types of hepatic cells. Pharmacological concentrations higher than 250 microU mL-1 exerted the opposite effect. In the case of human macrophages, an insulin concentration of 20 microU mL-1 increased cholesterol removal, whereas 100-200 microU mL-1 insulin inhibited cholesterol removal from cells, and very high concentrations (> 350 microU mL-1) again increased cholesterol removal. We have shown that insulin excess counteracts the beneficial effects of HDL in removing cellular cholesterol and, therefore, may promote development of atherogenesis.

Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice

“…39,40 In our study, we demonstrated that insulin inhibited cholesterol synthesis in peritoneal macrophages in a dose-dependent manner, both in the ex vivo and in the in vitro studies. Thus, the reduced macrophage cholesterol content in insulin supplemented mice may be attributable to the inhibition of cholesterol synthesis induced by insulin.…”

Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes

“…The effects of insulin on reverse cholesterol transport are incompletely understood. Insulin may inhibit cellular cholesterol efflux in vitro [17,18], as well as cholesterol uptake in hepatic cells, either directly [18] or by lowering hepatic lipase activity [19]. Little is known about the effects of insulin on plasma cholesterol esterification and (CET).…”

Insulin Suppresses HDL-Mediated Cholesterol Efflux from Macrophages Through Inhibition of Neutral Cholesteryl Ester Hydrolase and ATP-Binding Cassette Transporter G1 Expressions

“…HDL plays a pivotal role in cholesterol efflux, which is the initial step of reverse cholesterol transport (RCT) 26) ; however, the distinct mechanism of impaired RCT in type 2 diabetes is not well understood. Insulin has been reported to counteract cholesterol removal from human macrophages 23,27) and skin fibroblasts 28) , although the precise mechanism remains unclear.…”