Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

Shepherd, James; Caslake, Muriel; Lorimer, A. R.; Vallance, B D; Packard, C.J.

doi:10.1161/01.atv.5.2.162

Cited by 95 publications

(34 citation statements)

References 32 publications

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“…Treatment with fenofibrate results in a normalization of LDL composition, a decrease in the LDL FCR, and thereby an increase of the LDL cholesterol plasma level. Fenofibrate also induces a shift from small, dense to larger, buoyant LDLs (56). These observations were all confirmed in the present study.…”

Section: Discussionsupporting

confidence: 91%

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Bilz

Wagner

Schmitz

et al. 2004

Journal of Lipid Research

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Kinetics of apo B and apo AI were assessed in 8 patients with mixed hyperlipidemia at baseline and after 8 weeks of atorvastatin 80 mg q.d. and micronised fenofibrate 200 mg q.d. in a cross-over study. Both increased hepatic production and decreased catabolism of VLDL accounted for elevated cholesterol and triglyceride concentrations at baseline. Atorvastatin significantly decreased triglyceride, total, VLDL and LDL cholesterol and apo B concentrations ( ؊ 65%, ؊ 36%, ؊ 57%, ؊ 40% and ؊ 33%, respectively, P Ͻ 0.05). Kinetic analysis revealed that atorvastatin stimulated the catabolism of apo B containing lipoproteins, enhanced the delipidation of VLDL 1 and decreased VLDL 1 production. Fenofibrate lowered triglycerides and VLDL cholesterol ( ؊ 57% and ؊ 64%, respectively, P Ͻ 0.05) due to enhanced delipidation of VLDL 1 and VLDL 2 and increased VLDL 1 catabolism. Changes of HDL particle composition accounted for the increase of HDL cholesterol during atorvastatin and fenofibrate (18% and 23%, P Ͻ 0.01). Only fenofibrate increased apo AI concentrations through enhanced apo AI synthesis (45%, P Ͻ 0.05). We conclude that atorvastatin exerts additional beneficial effects on the metabolism of apo B containing lipoproteins unrelated to an increase in LDL receptor activity. Fenofibrate but not atorvastatin increases apo AI production and plasma turnover.

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Section: Discussionsupporting

confidence: 91%

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Bilz

Wagner

Schmitz

et al. 2004

Journal of Lipid Research

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“…Thus, in the absence of a functional LDLR, smaller VLDL particles containing fewer lipids should be produced. Accordingly, production of small dense VLDL particles is observed in FH (35).…”

Section: Discussionmentioning

confidence: 92%

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Gillian-Daniel

Bates

Tebon

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the low density lipoprotein (LDL) receptor (LDLR)cause hypercholesterolemia because of inefficient LDL clearance from the circulation. In addition, there is a paradoxical oversecretion of the metabolic precursor of LDL, very low density lipoprotein (VLDL). We recently demonstrated that the LDLR mediates presecretory degradation of the major VLDL protein, apolipoprotein B (apoB). Kinetic studies suggested that the degradation process is initiated in the secretory pathway. Here, we evaluated the ability of several LDLR variants that are stalled within the secretory pathway to regulate apoB secretion. Both a naturally occurring mutant LDLR and an LDLR consisting of only the ligand-binding domains and a C-terminal endoplasmic reticulum (ER) retention sequence were localized to the ER and not at the cell surface. In the presence of either of the ER-localized LDLRs, apoB secretion was essentially abolished. When the ligand-binding domain of the truncated receptor was mutated the receptor was unable to block apoB secretion, indicating that the inhibition of apoB secretion depends on the ability of the LDLR to bind to its ligand. These findings establish LDLR-mediated pre-secretory apoB degradation as a pathway distinct from reuptake of nascent lipoproteins at the cell surface. The LDLR provides an example of a receptor that modulates export of its ligand from the ER.M olecular defects in the low density lipoprotein (LDL) receptor (LDLR) cause Familial Hypercholesterolemia (FH), a condition associated with elevated plasma LDL cholesterol levels (1). Reduced expression, altered ligand binding, or defective transport to the cell surface all lead to a reduction in the functionally effective population of LDLRs at the cell surface.LDL is produced in the circulation from its precursor, very low density lipoprotein (VLDL). Apolipoprotein B (apoB) is the major protein component of VLDL and LDL. Two observations have suggested that the LDLR might be involved in apoB secretion. First, overproduction of apoB-containing lipoproteins occurs in some cases of FH (2-4). Second, drugs that lower LDL levels by increasing the expression of the LDLR (statins) in many instances have been shown to lower LDL without increasing LDL clearance; i.e., they lower LDL and͞or VLDL production (5).The proportion of apoB that escapes degradation within the secretory pathway primarily determines the rate of VLDL secretion. We recently demonstrated that the presence of the LDLR greatly increases the proportion of apoB subject to presecretory degradation. Our results directly link VLDL overproduction in FH with the loss of the LDLR (6).Several additional studies support a role for the LDLR in modulating apoB secretion. Increased secretion of VLDL is observed in vivo from both Ldlr Ϫ/Ϫ and transgenic Ldlr Ϫ/Ϫ mice that overexpress the nuclear form of sterol regulatory element binding protein-1a (SREBP-1a) and in vitro in hepatocytes from these animals (7). In contrast, transgenic SREBP-1a animals with a wild-type LDLR accumulate cholesterol a...

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“…In severely hypertriglyceridemic subjects, LDL particles are small and dense, and the low level of LDL in this condition is due to hypercatabolism of this species, probably by receptor-independent pathways. 1718 We found previously 19 that fibrate treatment suppressed this high rate of clearance, and we attributed this effect to a reduction in the amount of LDL degraded by the receptor-independent pathway, whereas LDL catabolism into the receptor route was increased. The overall impact of these changes is to increase the initially low levels of plasma LDL cholesterol, alter LDL composition, and increase the average LDL particle size.…”

mentioning

confidence: 74%

Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.

Packard

Murray

et al. 1993

Arterioscler Thromb

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107

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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...

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Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

Cited by 95 publications

References 32 publications

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Effects of atorvastatin versus fenofibrate on apoB-100 and apoA-I kinetics in mixed hyperlipidemia

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.

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