a CE, cholesteryl ester. b FC, free cholesterol. c PL, phospholipid. dTG, triglyceride.

LDL particle via IDL. Thus, the apoB-100 in LDL can also originate from VLDL. The apoB-100 comprises over 20% of the mass of an LDL particle (Table 2), and nearly half of the total mass is composed of FC (9%) and cholesteryl ester (38%).

Lipases, including phospholipase A2 (PLA2), also metabolize LDL. PLA2 is primarily produced by macrophages, and the majority of circulating plasma PLA2 is associated with LDL. The remodeling of LDL by PLA2 in effect creates a smaller, denser, modified LDL particle with a higher apoB content that can more easily penetrate peripheral tissue and deliver cholesterol by interaction with cellular scavenger receptors. The resulting intracellular FC is transformed to cholesteryl ester by the action of the enzyme, acyl-CoA:cholesterol acyltransferase (ACAT). These small, dense, modified LDL particles have been associated with an accompanying increased coronary risk. Increased plasma concentrations of PLA2 have also been linked to a higher CHD risk.

The heterogeneity of LDL particle populations has so far prevented any detailed, high-resolution, x-ray structural information from being elucidated by protein crystallography, although an informative spherical model has been developed from low-resolution data.11'12 As depicted in Figure 2, modeling indicates that apoB-100 surrounds the LDL particle with a thick, wide ribbon composed primarily of b-sheet that covers approximately 30% of the PL surface and occasionally penetrates below PL to interact with the neutral lipid core. Approximately 20% of the particle surface is covered by more helical components of apoB-100 that also form a protruding cap that acts as a ligand for the hepatic LDLr.11

Nearly 60% of the circulating cholesterol in human plasma is present as LDLc, and the majority of this cholesterol is removed from plasma through the liver via uptake by the LDLr.12,13 Indeed, functional mutations in the LDLr gene significantly decrease cholesterol clearance by this pathway and have been linked to the genetic disease, familial hypercholesterolemia (FH).14 The average human plasma concentration of LDLc in normal healthy subjects from one study was approximately 106 mg dL _ 1, accounting for nearly 60% of the total average plasma cholesterol levels of 170mgdL_ 1 (Table 3).13 In CHD patients with higher overall total plasma cholesterol levels, most of the excess cholesterol is found associated with LDLc.

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