Unesterified cholesterol accumulation

Interestingly, foam cells in advanced atherosclerotic lesions accumulate large amounts of unesterified cholesterol [9,17], some of which is in crystalline form and may be deposited in the extracellular space when foam cells die (Fig. 3). For example, while 2 of 13 abdominal aortic and femoral artery fatty streak lesions contained cholesterol crystals, all of 24 advanced lesions had these structures [17]. The mechanism of unesterified cholesterol accumulation is not known, but could involve either defects in cholesterol trafficking to... 

Fig. 3. (A) Intracellular unesterified cholesterol accumulation in a lesional foam cell. Electron micrograph of the cytoplasm of a foam cell isolated ftom an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. The cell was treated with filipin, which forms spicules with unesterified cholesterol. Multiple spicules are observed in vesicles, shown to be lysosomes (depicted by arrows). D , neutral lipid droplet. Bar 0.5 pm. From [34]. Lab. Invest. 41 160-167. (B) Extracellular cholesterol crystals in an advanced atherosclerotic lesion. The section is from the proximal aorta of a fat-fed apolipoprotein E knockout mouse. This mouse model is often used to study atherosclerosis in vivo because the high plasma levels of remnant lipoproteins resulting from absence of apolipoprotein E leads to a much greater degree of atherosclerosis lesion development than observed in wild-type mice. The arrows depict the areas of cholesterol crystals. Reproduced with permission from the publisher.

HDL uptake of unesterified cholesterol Nascent HDL are diskshaped particles containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They are rapidly converted to spherical particles as they accumulate cholesterol (Figure 18.23). [Note HDL particles are excellent acceptors of unesterified cholesterol (both from other lipoproteins particles and from cell membranes) as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol.]... 

Atherosclerosis is believed to be predominantly an inflammatory condition produced as a response to injury (Elkind, 2006). Atherosclerosis is defined by the accumulation in the arterial intima of mainly low-density lipoprotein (LDL)-derived lipids along with apolipoprotein B-lOO (apoBlOO). LDL is the major carrier of cholesterol in the circulation and is composed of one apoB-100 together with phosphatidylcholine (PC), sphingomyelin (SM) and unesterified cholesterol (500 200 400 molecules respectively) constituting a surface film surrounding a core of cholesteryl esters and triacylglycerols. 

There are conflicting data on whether the availability of cholesterol and/or cholesteryl esters directly influences apo B secretion. Several studies have suggested that cholesterol supply can regulate VLDL secretion. For example, VLDL production in animals and man is decreased by statin treatment, and inhibition of cholesterol synthesis by a statin, an inhibitor of the rate-limiting step of cholesterol biosynthesis (Chapter 14), reduced VLDL secretion in perfused rat livers (M. Heimberg, 1990) and primary hepatocytes. However, this effect of statins can perhaps be ascribed to increased expression of LDL receptors rather than to a reduction in cholesterol synthesis (Section 7.1). Depletion of cholesterol in rodent hepatocytes by the ABCAl-dependent lipidation of apo A1 (Chapter 19) also decreases VLDL secretion (R. Lehner, 2004). Furthermore, the secretion of apo BlOO-containing VLDLs is increased in primary hepatocytes derived from Niemann-Pick Cl-deficient mice. Niemann-Pick Cl-deficiency causes a severe defect in trafficking of unesterified cholesterol out of the lysosomal/endosomal pathway and consequently, Niemann-Pick Cl-deficient hepatocytes accumulate 5- to 10-fold more unesterified cholesterol than do wild-type hepatocytes. In hepatocytes from Niemann-Pick Cl-deficient mice, cholesterol synthesis is increased and the rate of cholesterol esterification and the amount of the transcriptionally active form of SREBP-1 are also increased (J.E. Vance, 2007). However, because of multiple alterations in lipid metabolism in these hepatocytes, increased VLDL secretion cannot be attributed specifically to increased synthesis of cholesterol or cholesteryl esters. 

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. 

HDL carry cholesterol from peripheral cells to the liver (Figure 4), a process generally referred to as reverse cholesterol transport. This process enables the removal by HDL of unesterified cholesterol that may have accumulated in cell membranes and plasma lipoproteins, and its transport to the liver, where it is degraded and used to synthesize bile acids (Frayn, 2003). 

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