Macrophages unesterified cholesterol

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

Kritharides L, Jessup W, Mander EL, et al. (1995) Apohpoprotein A-I-mediated efflux of sterols from oxidized LDL-loaded macrophages. Arterioscler ThrombArterioscler Thromb Vase Biol 15 276-289 Kruth HS (1984) Localization of unesterified cholesterol in human atherosclerotic lesions. Demonstration of... 

Fig. 8. Phospholipid whorls in cholesterol-loaded macrophages. (A) Electron micrograph showing a membrane whorl in the cytoplasm of a foam cell. The cell was isolated from an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. From [34]. Lab. Invest. 41 160-167. (B) Electron micrograph showing a membrane whorl in the cytoplasm of a cholesterol-loaded J774 macrophage. The cell was in the adaptive stage, i.e., before the onset of unesterified cholesterol-induced death. From Shiratori et al. (1994). J. Biol. Chem. 269 11337-11348. Reproduced with permission from the publisher.

It has been hypothesized that HDL absorb unesterified cholesterol by physicochemical mechanisms from macrophage cell membranes and other cholesterol-enriched cells. This leads to an imbalance between cytoplasmic cholesterol and cell surface cholesterol equilibrium is restored by movement of cholesterol from the cytoplasmic pool. 

In addition, cholesterol accumulation in macrophages, mediated by modified lipoproteins (e. g., acetylated low-density lipoprotein, AcLDL), stimulates these cells to synthesize and secrete apolipoprotein (Apo) E/phospholipid discs. During the intraplasmatic cholesterol esterification process mediated by lecithinxholesterol acyltransferase (LCAT), HDL are assumed to incorporate unesterified cholesterol from the cell surface and Apo E from secreted Apo E/phospholipid discs and thereby mediate reverse cholesterol transport from peripheral cells back to the liver. The resulting cholesteryl ester- and Apo E-enriched HDLi are transported to the liver where they may be recognized by a hepatic Apo E receptor. 

Fig. 2. Cholesterol metabolism in macrophages. AcLDL, Acetyl LDL EC = esterified cholesterol UC = unesterified cholesterol RER, SER, rough, smooth endoplasmic reticulum...

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