Abstract
Insulin resistance, obesity, and diabetes are characterized by hyperglycemia, hyperinsulinemia, and hyperleptinemia and are associated with increased risk of atherosclerosis. In an effort to understand how this occurs, we have investigated whether these factors cause disregulation of cholesterol ester metabolism in J774.2 macrophages. Raising glucose levels alone was sufficient to increase uptake of acetylated low density lipoprotein but did not stimulate synthesis of cholesterol esters. In the presence of high glucose, both insulin and leptin increased the rate of cholesterol ester synthesis, although they did not further increase uptake of acetylated low density lipoprotein. However, in the presence of high glucose both insulin and leptin caused a significant increase in the activity of acyl-CoA: cholesterol O-acyltransferase (ACAT) combined with a significant reduction in the level of hormone-sensitive lipase (HSL). Because ACAT is the main enzyme responsible for cholesterol ester synthesis and HSL contributes significantly to neutral cholesterol ester hydrolase activity, this suggests that glucose primes the J774.2 cells so that in the presence of high insulin or leptin they will store cholesterol esters. This contrasts with 3T3-L1 adipocytes, where HSL activity and expression are increased by insulin in high glucose conditions. These findings may provide an explanation for the observation that in conditions characterized by hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in adipocytes is increased while hydrolysis of cholesterol esters in macrophages is decreased, contributing to foam cell formation.
Highlights
Insulin resistance, obesity, and diabetes are characterized by hyperglycemia, hyperinsulinemia, and hyperleptinemia and are associated with increased risk of atherosclerosis
These findings may provide an explanation for the observation that in conditions characterized by hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in adipocytes is increased while hydrolysis of cholesterol esters in macrophages is decreased, contributing to foam cell formation
Effects of Glucose, Leptin, and Insulin on Cholesterol Ester Synthesis—We investigated the effects of leptin, insulin, and glucose on cholesteryl esters (CEs) metabolism in macrophages
Summary
Important to understand the mechanisms affecting the activity of this enzyme. The effects of glucose, insulin, and leptin on the mechanisms regulating CE metabolism in macrophages have not been well studied. There are no reports of effects of these factors on LDL uptake or ACAT activity in macrophages, the recent finding that increasing glucose concentrations cause an increase in the expression of the CD36 scavenger receptor indicates that hyperglycemia might have a direct role in stimulating LDL uptake [22]. We have recently reported that insulin and leptin acutely stimulate HSL activity in J774.2 macrophages [23], suggesting they may have a regulatory role in CE metabolism in these cells. We have investigated whether glucose levels, in combination with high levels of insulin or leptin, might effect CE synthesis in macrophages and whether there are detectable effects on cholesterol uptake, ACAT activity, or HSL activity in these cells
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