Metabolic basis of primary hypercholesterolemia

Abstract

Background: Hypercholesterolemia is a well-established risk factor for coronary heart disease. However, the mechanisms underlying hypercholesterolemia, elevated low density lipoprotein (LDL) in particular, are not well understood. To determine these mechanisms, we studied LDL kinetics in a group of men with primary hypercholesterolemia.

Methods and results: LDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol, 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol, more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in LDL apolipoprotein (apo) B levels but had abnormally high LDL cholesterol-to-apo B ratios; 14 patients had very low fractional catabolic rates (FCRs) for LDL, similar to FH patients; 35 patients had FCRs for LDL in the borderline range but high production rates for LDL; and 22 patients had a high flux of LDL (high production rates and high FCRs). In general, patients with severe hypercholesterolemia resembled those with moderate LDL elevations, except that their LDL particles were enriched with cholesterol.

Conclusions: Data from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia. These patterns can serve as the basis for further investigation to determine the molecular defects responsible for each pattern.