Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.

Abstract

Metabolic heterogeneity in low density lipoprotein (LDL) may be detected 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 plasma, whereas the second (pool B) is catabolized more slowly. In the present 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 pretreatment high LDL levels in the hypercholesterolemic subjects resulted from an accumulation of apoprotein-LDL (apo-LDL) mass in pool B (2,077 ±174 mg versus 787 ±70 mg in normal subjects, p< 0.002). Pool A apo-LDL was present at normal levels (-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 cholesterol (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 circulating apo-LDL mass (2,312 ±200 mg versus 3,279 ±264 mg before treatment, 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 pretreatment 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 resulted from a drug-induced decrease in the particle size of very low density lipoprotein made by the liver, which in turn favored the formation of more rapidly catabolized LDL. Overall, the rate of apo-LDL degradation 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 catabolism via the receptor-mediated pathway but also, by lowering plasma triglyceride levels, inhibits the formation of slowly metabolized, potentially atherogenic LDL particles. L ow density lipoprotein (LDL), the major cholesterol carrier in human plasma, plays a critical role in the initiation and progression of atherosclerotic lesions. Until recently, studies of the structure, function, and metabolism 1 of this lipoprotein assumed it to be a homogeneous entity. However, it has now been demonstrated that LDL exists in the plasma of normal and hyperlipidemic individuals as a heterogeneous population of particles that are usually divided into three subtractions on the basis of size and density. -4 Preliminary investigations have indicated that these fractions have distinct properties. LDL-I, the largest and most buoyant, is present in high concentra...

Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome

“…The mechanism for increased catabolism of all apoBcontaining lipoproteins with fenofibrate was probably chiefly due to hepatic activation of PPAR-␣ (19). Increased expression of lipoprotein lipase (23) and decreased hepatic apoCIII synthesis (27) could partly explain the increase in FCR of VLDL apoB and IDL apoB, respectively, as well as the increased production of LDL apoB (42,43). The fall in plasma lathosterol agrees with work showing that fibrates suppress cholesterol biosynthesis by inhibiting HMGCoA reductase (47).…”

“…In volunteers with comparable characteris- tics to our population, bezafibrate increased the production and catabolism of LDL apoB (42). The same group later showed that fenofibrate increases the catabolism of VLDL 1 , reducing its conversion of VLDL 2, and also accelerates the production and catabolism of LDL 2 , consistent with a distribution of LDL particles to a larger less dense type (43). Fibrates have also been demonstrated to increase the synthesis of apoAI in familial hyperlipidemias (44,45), but not all reports have been consistent.…”

Low-density lipoprotein subclasses: mechanisms of formation and modulation

“…This enzyme has a pivotal role in the remodelling of large LDL into small LDL through its action on LDL-TAG. Hence, LDL subclasses were shown to redistribute at about a TAG threshold of 1-5mmol/l, a finding concordant with the influence of TAG-lowering drugs (Superko & Gauss, 1992;Caslake et al 1993). This relatively low TAG value has been ascribed clinical significance in NIDDM (Lahdenpera et al 1996) and in the expression of small, dense LDL in an ALP (Austin et al 1990), suggesting that current action limits for intervention may be too high.…”

Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism

“…10 Fibrate treatment results in a reduction of the LDL fraction of atherogenic small, dense particles with an equivalent increase in the intermediate subfraction. [11][12][13] Within the triglyceride-rich apolipoprotein (apo) B-containing lipoproteins, fibrates efficiently reduce the apoC-III-containing particles, 14,15 which are markers for increased risk for atherogenesis. 16 The increased HDL concentrations after fibrates are generally reflected by increased plasma levels of apoA-I and apoA-II, 14,15 a change that is associated with an increase in lipoprotein (Lp) A-I:A-II, and a decrease in LpA-I concentrations in patients treated with fenofibrate.…”