FENOFIBRATE AND LDL METABOLIC HETEROGENEITY IN HYPERCHOLESTEROLEMIA

Metabolic heterogeneity in low density lipoprotein (LDL) may be detect ed by examination of the daily urinary excretion rate of radioactivity after injection of trace-labeled lipoprotein. Two distinct pools are observed within LDL. The first (pool A) is cleared rapidly from the pl asma, whereas the second (pool B) is catabolized more slowly. In the p resent study we examined LDL metabolism in seven hypercholesterolemic subjects (six women and one man) before and during fenofibrate therapy . Comparison with normocholesterolemic individuals showed that the pre treatment high LDL levels in the hypercholesterolemic subjects resulte d from an accumulation of apoprotein-LDL (apo-LDL) mass in pool B (2,0 77+/-174 mg versus 787+/-70 mg in normal subjects, p<0.002). Pool A ap o-LDL was present at normal levels (approximately 1,000 mg), although its fractional catabolic rate was reduced (0.39+/-0.06 versus 0.61+/-0 .03 pool/day in normal subjects, p<0.01). Fenofibrate therapy (100 mg t.i.d. for 8 weeks) produced substantial reductions in plasma choleste rol (29%; p<0.001), triglycerides (36%;p<0.001), and LDL cholesterol ( 30%;p<0.001). The latter was associated with a 30% decrease in circula ting apo-LDL mass (2,312+/-200 mg versus 3,279+/-264 mg before treatme nt, p<0.005). This resulted from a combination of two effects. First, although overall LDL apoprotein B production did not change, there was a shift from pool B to pool A. Pool A input was 400+/-74 mg/day pretr eatment versus 706+/-62 mg/day on fenofibrate; pool B input was 422+/- 35 mg/day pretreatment versus 258+/-41 mg/day on the drug. At the same time, catabolism of pool A rose from 0.39+/-0.06 to 0.66+/-0.08 pool/ day (p<0.05). We hypothesize that the shift from pool B to pool A resu lted from a drug-induced decrease in the particle size of very low den sity lipoprotein made by the liver, which in turn favored the formatio n of more rapidly catabolized LDL. Overall, the rate of apo-LDL degrad ation by the receptor route (as detected using a combination of native and 1,2-cyclohexanedione-modified LDL tracers) rose 43% on the drug, whereas the amount cleared by the receptor-independent pathway did not change. Fenofibrate, therefore, appears not only to promote LDL catab olism via the receptor-mediated pathway but also, by lowering plasma t riglyceride levels, inhibits the formation of slowly metabolized, pote ntially atherogenic LDL particles.