Cholesterol esters macrophages

An old hypothesis is based on the observations of Dahlen et al. (D3), who demonstrated that above a certain concentration in plasma, Lp(a) could bind to glycosaminoglycans in the arterial wall (B12). Colocalization of Lp(a) and fibrin on the arterial wall can lead to oxidative changes in the lipid moiety of Lp(a) and induce the formation of oxidatively modified cholesterol esters, which in turn can influence the interaction of Lp(a) and its receptors on macrophages. This process is promoted by the presence of calcium ions. Cushing (C14), Loscalzo (L22), and Rath (R3) reported a colocalization of undegraded Lp(a) and apo-Bl00 in the extracellular space of the arterial wall. In contrast to LDL, Lp(a) is a substrate for tissue transglutaminase and Factor XUIa and can be altered to products that readily interact with cell surface structures (B21). 

Beauveriolides I (19) and III (20), two fungal (Beauveria Spp) metabolites, have been found to be specific inhibitors of lipid droplet formation in mouse macrophages. It has been recently observed that the metabolisms of A[3 proteins and cholesterol esters are closely linked. One of the... 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

As a result of hypercholesterolemia, an intracellular accumulation of cholesteryl esters occurs, which is associated with the initiating events of atherogenesis, in particular, foam cell generation, which involves the intracellular accumulation of large amounts of cholesterol within macrophages and smooth muscle cells of aorta (76). 

Atherosclerosis involves the formation of lipid-rich plaques in the intima of arteries. The plaques begin as fatty streaks containing foam cells, which initially are macrophages filled with lipids, particularly cholesterol esters. These early lesions develop into fibrous plaques that may occlude an artery and cause a myocardial infarct or a cerebral infarct. Formation of these plaques is often associated with abnormalities in... 

Figure 26-21 Reverse cholesterol transport pathway. HDl High-density lipoproteins LDL, low-density lipoproteins tDL, intermediate-density lipoproteins HTL, hepatic lipoprotein lipase LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein apo E, apoiipoprotein E. Cholesterol is removed from macrophages and other arterial wall cells by an HDL-mediated process. The LCAT esterifies the cholesterol content of HDL to prevent it from reentering the ceils. Cholesterol esters are delivered to the liver by one of three pathways ( ) cholesterol esters are transferred from HDL to LDL by CETP and enter the liver through the specific LDL receptor pathway (2) cholesterol esters are selectively taken from HDL by HDL receptors and HDL particles are returned to circulation for further transport or (3) HDL have accumulated apo E and therefore the particles can enter the liver through remnant receptors, (From Gwynne JT. High density lipoprotein cholesterol levels as a marker of reverse cho/estero/ tronsport./ m j Cardiol I989 64 10G-I7G. Copyright 1989, with permission from Excerpta Medico Inc.)...

Huang et al. (1993) cite many studies that demonstrate that n-6 fatty acid are able to reduce the level of cholesterol in the blood serum. The data of Horrocks and Harder (1993) showed that n-6 fatty acids and n-3 fatty acids differ in their mode of action in cholesterol reduction, such that n-6 fatty acids redistribute cholesterol and n-3 fatty acid actually reduces the level of cholesterol. Davis (1992) demonstrated that n-3 essential fatty acids are more effective in reducing cholesterol levels in macrophages than n-6 essential fatty acids, most probably by the differential effect on the enzyme acyl-CoA (cholesterol acyltransferase). However, Horrocks and Harder (1983) indicated that cholesterol-esterifying enzymes that incorporate free fatty acids into cholesterol esters without the participation of CoA are also present in the rat brain. 

Macrophage yS-VLDL receptors may serve a back-up function in cholesterol clearance by facilitating removal of cholesterol-rich ]S-VLDL particles which accompany diet-induced hypercholesterolemia. When dog plasma cholesterol levels exceed 750 mg/dl, )8-VLDL accumulate in plasma and macrophages accumulate cholesterol and cholesterol esters [60]. The association of these events suggests that -VLDL may be taken up by macrophage j8-VLDL receptors for the deposition of plasma cholesterol esters. 

The acetyl-LDL receptor is distinct from the LDL receptor. Acetyl-LDL can be precipitated by antibody raised against LDL, yet is not taken up by the LDL receptor [64]. By contrast, LDL is taken up by macrophages only at a low rate without accumulation of cholesterol esters [19,61]. Unlike the LDL receptor, the acetyl-LDL receptor does not require divalent cations for uptake [19]. In addition, monocytes from normal subjects exhibit an acetyl-LDL receptor activity comparable to that of monocytes from patients with LDL receptor-negative homozygous FH. 

The only receptor-mediated uptake process regulated in macrophages involves suppression of )8-VLDL receptors. This suppression only occurs after extensive cholesterol ester accumulation and can be induced by either j8-VLDL or chemically modified LDL [13]. Lipoprotein uptake by all known receptor systems in macrophages causes a marked stimulation of ACAT activity which results in the massive accumulation of cholesteryl ester droplets in the cytoplasm [13]. Free cholesterol can be excreted from the macrophage if cholesterol-accepting Upoproteins such as HDL are present. The uncontrolled uptake and deposition of cholesteryl esters in macrophages is believed to be the key to formation of the foam cells which are associated with atherosclerosis. 

Atherosclerotic plaques The protruding masses that form on the inner walls of arteries in atherosclerotic disease. A mature plaque consists partly of lipid, mainly cholesterol esters, which may be free or contained in lipid-engorged macrophages called foam cells, and partly of an abnormal proliferation of smooth-muscle and connective-tissue cells. 

Kondo E, Kanai K (1976) Accumulation of cholesterol esters in macrophages incubated with mycobacteria in vitro. Jpn J Med Sci Biol 29 123-137... 

Okazaki H, Osuga J, Tsukamoto K, et al. Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase. J Biol Chem 2002 277 31,893-31,899. 

The discovery that LDL receptor deficiency in familial hypercholesterolemia is associated with premature atherosclerosis was initially paradoxical. A hallmark of atherosclerotic lesions is the formation of foam cells — macrophages and smooth muscle cells that accumulate cytoplasmic cholesterol ester droplets. If these cells lack the LDL receptor, how do they import excessive amounts of cholesterol ... 

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