Lipoprotein-derived cholesterol, intracellular

Cholesterol accumulation in lesional macrophages intracellular trafficking of lipoprotein-derived cholesterol... 

The trafficking of lipoprotein-derived cholesterol from lysosomes has been a major area of focus in the field of intracellular cholesterol metabolism, and many of the cellular and molecular events are not known (Chapter 17). By analyzing cells with mutations in cholesterol transport, investigators have identified roles for two proteins, called NPCl and NPC2 (HEl), in lysosomal and/or endosomal cholesterol transport (E.J. Blanchette-Mackie, 2000 P. Lobel, 2000). In addition, the lipid lysobisphosphatidic acid and certain GTPases called Rab proteins may also play roles in these processes (J. Gruenberg, 1999 E. Ikonen, 2006). The mechanisms by which these molecules are involved in cholesterol transport, however, are poorly understood [14]. 

Acyl-CoA cholesterol acyl transferase (ACAT) catalyzes the intracellular formation of cholesteryl esters (CE) in all mammalian cells. It has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-laden macrophages. The accumulation of CE in macrophage-derived foam cells is characteristic of the early step in the development of atherosclerosis. ACAT inhibitors reduced TC levels without affecting HDL-C. This can be attributed to decreased intestinal cholesterol absorption based on binding to bile acid (Turley SD. and Herndon MW. 1994)... 

Fatty acids are also found esterified to the 3-hydroxyl group of cholesterol (cholesterol esters ChE). ChE, which are more hydrophobic than free cholesterol, are a transport and storage form of cholesterol. ChE are found in high concentrations in low-density lipoproteins. Intracellular lipid droplets containing ChE are found in steroidogenic tissues and are thought to be a reservoir of cholesterol for steroid-hormone synthesis. The fatty acid most commonly found in ChE is 18 1. It must be activated to its CoA derivative before transfer to cholesterol in a reaction catalyzed by acyl-CoA cholesterol acyltransferase. ChE are also formed within lipoproteins by the transfer of one fatty acyl chain from phosphatidyl choline to cholesterol, a reaction catalyzed by circulating lecithin cholesterol acyltransferase. 

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