Abstract
The influence of the hypercholesterolemia associated with atherosclerosis on monocytes is poorly understood. Monocytes are exposed to high concentrations of lipids, particularly cholesterol and lysophosphatidylcholine (lyso-PC). Indeed, in line with recent reports, we found that monocytes accumulate cholesteryl esters (CEs) in hypercholesterolemic mice, demonstrating the need for studies that analyze the effects of lipid accumulation on monocytes. Here we analyze the effects of cholesterol and lyso-PC loading in human monocytes and macrophages. We found that cholesterol acyltransferase and CE hydrolase activities are lower in monocytes. Monocytes also showed a different expression profile of cholesterol influx and efflux genes in response to lipid loading and a different pattern of lyso-PC metabolism. In monocytes, increased levels of CE slowed the conversion of lyso-PC into PC. Interestingly, although macrophages accumulated glycerophosphocholine, phosphocholine was the main water-soluble choline metabolite being generated in monocytes, suggesting a role for mono- and diacylglycerol in the chemoattractability of these cells. In summary, monocytes and macrophages show significant differences in lipid metabolism and gene expression profiles in response to lipid loading. These findings provide new insights into the mechanisms of atherosclerosis and suggest potentials for targeting monocyte chemotactic properties not only in atherosclerosis but also in other diseases.
Highlights
The influence of the hypercholesterolemia associated with atherosclerosis on monocytes is poorly understood
When we analyzed the expression of the scavenger receptor (SR) cluster of differentiation 36 (CD36) and scavenger receptor class A type 1 (SR-A1), we found that cholesteryl ester (CE)/lyso-PC micelles induced a significant increase in the expression of the CD36 only in monocytes (Fig. 4D, dark gray bars), but no changes were found for the SR-A1 gene expression in any of the conditions (Fig. 4C)
We provide evidence showing that monocyte properties are altered by hypercholesterolemia in a different manner than in macrophages
Summary
The influence of the hypercholesterolemia associated with atherosclerosis on monocytes is poorly understood. Excess free cholesterol is reesterified on the endoplasmic reticulum by ACAT1 [13, 14], and stored in cytoplasmic lipid droplets This lipid-scavenging function of macrophages is initially beneficial, but under conditions of unregulated or increased lipid uptake, it leads to excessive accumulation of CE in macrophages that results in foam cell formation [14, 15]. In this way, acceptormediated cholesterol efflux plays a key role in protecting against atherosclerosis.
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