Metabolic Origins and Clinical Significance of LDL Heterogeneity

LDLs in humans comprise multiple distinct subspecies that differ in their metabolic behavior and pathologic roles. Metabolic turnover studies suggest that this heterogeneity results from multiple pathways, including catabolism of different VLDL and IDL precursors, metabolic remodeling, and direct production. A common lipoprotein profile designated atherogenic lipoprotein phenotype is characterized by a predominance of small dense LDL particles. Multiple features of this phenotype, including increased levels of triglyceride rich lipoprotein remnants and IDLs, reduced levels of HDL and an association with insulin resistance, contribute to increased risk for coronary heart disease compared with individuals with a predominance of larger LDL. Increased atherogenic potential of small dense LDL is suggested by greater propensity for transport into the subendothelial space, increased binding to arterial proteoglycans, and susceptibility to oxidative modification. Large LDL particles also can be associated with increased coronary disease risk, particularly in the setting of normal or low triglyceride levels. Like small LDL, large LDL exhibits reduced LDL receptor affinity compared with intermediate sized LDL. Future delineation of the determinants of heterogeneity of LDL and other apoB-containing lipoproteins may contribute to improved identification and management of patients at high risk for atherosclerotic disease.