Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects

Stewart, James; Packard, Christopher J.; Lorimer, A. R.; Boag, D E; Shepherd, James

doi:10.1016/0021-9150(82)90010-7

Cited by 106 publications

(29 citation statements)

References 19 publications

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“…This usually implies an expanded cellular requirement for cholesterol and is consistent with the finding that fenofibrate inhibits the action of 3-hydroxy-3-methylglutaryl CoA reductase 34 and therefore presumably suppresses endogenous sterol synthesis. The response of the receptor pathway to fenofibrate therapy is similar to that which we observed 35 in a group of Type II hyperiipoproteinemic subjects prescribed an alternative clofibrate analogue, bezafibrate.…”

Section: Discussionsupporting

confidence: 80%

“…In a previous publication 35 we proposed that the primary action of clofibrate and its analogues can be adequately explained on the basis of their effects on two key enzymes in lipoprotein metabolism -lipoprotein lipase and 3-hydroxy-3-methylglutaryl CoA reductase. The results of the present study remain consistent with that view and provide a working hypothesis to explain the actions of these drugs in the treatment of the various hyperlipoproteinemias.…”

Section: Discussionmentioning

confidence: 99%

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Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

Shepherd¹,

Caslake²,

Lorimer³

et al. 1985

Arteriosclerosis

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This study examines the kinetic basis for the increment in plasma low density lipoprotein (LDL) levels that accompanies the fenofibrate treatment of severely hypertriglyceridemic (HTG) patients. Seven HTG men with a mean plasma triglyceride level of 1470 mg/dl were treated for 6 weeks. During treatment, their plasma triglyceride level fell by 77% and their cholesterol level by 41%. The fall in very low density lipoprotein (VLDL) cholesterol level was reciprocated by increments in the cholesterol level in both LDL and high density lipoproteins (HDL); the rise in HDL was confined to HDL 3 . LDL catabolism was examined before and during therapy using native and chemically modified tracers in an attempt to distinguish receptor-mediated from nonreceptor-mediated clearance. In their basal state, the hypertriglyceridemic subjects overcatabolized both the native and the modified lipoprotein, implying that the nonreceptor pathways were hyperactive. The mean fractional clearance rate of LDL via the receptor pathway was not significantly different from normal. Fenofibrate therapy corrected the patients' hypercatabolism, reducing the receptor-independent fractional clearance of apo LDL by 50% (from 0.48 to 0.24 pools/day; p < 0.05). The mean fractional catabolic activity of the receptor route did not change, but when the increment in the plasma apo LDL concentration was taken into account, it was clear that the drug treatment was associated with an increase in the net amount cleared by the receptor pathway and with a reduction of lipoprotein uptake into receptor-independent routes. (Arteriosclerosis 5:162-168, March/April 1985)

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

Shepherd¹,

Caslake²,

Lorimer³

et al. 1985

Arteriosclerosis

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show abstract

“…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).…”

Section: Regulation Of Apoai and Apob-100 Kineticssupporting

confidence: 78%

“…Fibrates have been shown to decrease VLDL apoB production and increase VLDL apoB catabolism in markedly hypertriglyceridemic subjects (40,41). 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).…”

Section: Regulation Of Apoai and Apob-100 Kineticssupporting

confidence: 70%

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

et al. 2003

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The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d 3 -leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL 2 cholesterol (P < 0.001), HDL 3 cholesterol (P < 0.01), apoAI (P ‫؍‬ 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P ‫؍‬ 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome. Diabetes 52:803-811, 2003

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“…[9][10][11] The large-scale, 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) demonstrated that bezafibrate slowed the progression of coronary atherosclerosis, and reduced coronary events in young survivors of myocardial infarction; 12,13 bezafibrate effectively lowered the serum very low density lipoprotein (VLDL)-TG, VLDL-C, and fibrinogen levels, but no change was observed in low density lipoprotein-cholesterol (LDL-C). Therefore, some factor (s) other than LDL-C may play important roles in the progression/regression of coronary lesions.…”

mentioning

confidence: 99%

Combined Effects of Probucol and Bezafibrate on Lipoprotein Metabolism and Liver Cholesteryl Ester Transfer Protein mRNA in Cholesterol-Fed Rabbits

Saku

Jimi

et al. 1999

Jpn Circ J

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Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects

Cited by 106 publications

References 19 publications

Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.

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

Combined Effects of Probucol and Bezafibrate on Lipoprotein Metabolism and Liver Cholesteryl Ester Transfer Protein mRNA in Cholesterol-Fed Rabbits

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