Abstract
Esterification of cholesterol is a universal mechanism to store and transport large quantities of cholesterol between organs and tissues and to avoid toxicity of the excess of cellular cholesterol. Intended for transport and storage and thus to be inert, cholesteryl esters (CEs) reside in hydrophobic cores of circulating lipoproteins and intracellular lipid droplets. However, the inert identity of CEs is dramatically changed if cholesterol is esterified to a polyunsaturated fatty acid and subjected to oxidative modification. Post-synthetic, or epilipidomic, oxidative modifications of CEs are mediated by specialized enzymes, chief among them are lipoxygenases, and by free radical oxidation. The complex repertoire of oxidized CE (OxCE) products exhibit various, context-dependent biological activities, surveyed in this review. Oxidized fatty acyl chains in OxCE can be hydrolyzed and re-esterified, thus seeding oxidized moieties into phospholipids (PLs), with OxPLs having different from OxCEs biological activities. Technological advances in mass spectrometry and the development of new anti-OxCE antibodies make it possible to validate the presence and quantify the levels of OxCEs in human atherosclerotic lesions and plasma. The article discusses the prospects of measuring OxCE levels in plasma as a novel biomarker assay to evaluate risk of developing cardiovascular disease and efficacy of treatment.
Highlights
Cholesterol esterification is a mechanism the body uses to store and transfer cholesterol, while at the same time to avoid cellular toxicity of the excess of unesterified cholesterol
Biological activity and biomarker potential of oxidized CE (OxCE) remain understudied. This is due to a common perception of cholesteryl ester (CE) as inherently inert intracellular “storage” and lipoprotein “transport” lipids, which is certainly the case for CEs with saturated fatty acyls
We reviewed how cholesterol binding to MD-2 makes OxCE an agonist for TLR4, resulting in inflammatory and lipid accumulation responses in macrophages
Summary
Cholesterol esterification is a mechanism the body uses to store and transfer cholesterol, while at the same time to avoid cellular toxicity of the excess of unesterified (often called free) cholesterol. The strategy for storage and transport of amphipathic cholesterol molecules is their esterification to fatty acids and tight packaging of the resulting hydrophobic CEs in the core of intracellular lipid droplets or circulating lipoproteins (Figure 1—Transport and Storage). After a threshold level in cellular cholesterol mass has been reached, excess cholesterol is esterified in the ER by the enzyme acyl CoA cholesterol acyltransferase (ACAT), and the newly synthesized CEs are stored in lipid droplets. In plasma of healthy human subjects, approximately 70% of cholesterol molecules are esterified and reside in lipoprotein cores [10, 11] This abridged description of CE metabolism illustrates complex pathways involved in keeping CE locked away in hydrophobic cores of lipid droplets and lipoproteins for storage and safe passage through the body—that is until CE undergoes oxidation and becomes biologically active
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