The Experts below are selected from a list of 255 Experts worldwide ranked by ideXlab platform
Daniel J. Rader - One of the best experts on this subject based on the ideXlab platform.
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HDL and cardiovascular disease
The Lancet, 2014Co-Authors: Daniel J. Rader, G. Kees HovinghAbstract:The Cholesterol contained within HDL is inversely associated with risk of coronary heart disease and is a key component of predicting cardiovascular risk. However, despite its properties consistent with atheroprotection, the causal relation between HDL and atherosclerosis is uncertain. Human genetics and failed clinical trials have created scepticism about the HDL hypothesis. Nevertheless, drugs that raise HDL-C concentrations, cholesteryl ester transfer protein inhibitors, are in late-stage clinical development, and other approaches that promote HDL function, including reverse Cholesterol transport, are in early-stage clinical development. The final chapters regarding the effect of HDL-targeted therapeutic interventions on coronary heart disease events remain to be written. © 2014 Elsevier Ltd.
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Cholesterol efflux and atheroprotection advancing the concept of reverse Cholesterol transport
Circulation, 2012Co-Authors: Robert S. Rosenson, Bryan H Brewer, Sean W Davidson, Zahi A Fayad, Valentin Fuster, James A Goldstein, Marc K Hellerstein, Xiancheng Jiang, Michael C Phillips, Daniel J. RaderAbstract:High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage Cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities.1 HDL particles are critical acceptors of Cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net Cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial Cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage Cholesterol efflux and disposition of Cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated Cholesterol efflux,2,3 the concentration of the Cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse Cholesterol transport” (RCT) process; however, macrophage-derived Cholesterol represents a minor component of the Cholesterol transported by HDL particles.4–7 One important pathway for Cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and Cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) A-I complexes (pre-β migrating HDL or very small HDL [HDL-VS]; Figure 2).1,8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage Cholesterol efflux through interactions (Figure 3) with spherical, Cholesterol-containing α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDL-VL).1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of Cholesterol in lipid-laden macrophages. A more established role for SR-BI in Cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this Cholesterol …
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effects of an inhibitor of cholesteryl ester transfer protein on hdl Cholesterol
The New England Journal of Medicine, 2004Co-Authors: Margaret E Brousseau, Ernst J Schaefer, Megan L Wolfe, Leanne T Bloedon, Andres Digenio, Ronald W Clark, James P Mancuso, Daniel J. RaderAbstract:background Decreased high-density lipoprotein (HDL) Cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL Cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL Cholesterol levels. methods We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL Cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks. results Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL Cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL Cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) Cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of Cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort.
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High-density lipoprotein metabolism: Molecular targets for new therapies for atherosclerosis
Current Atherosclerosis Reports, 2000Co-Authors: Masa-aki Kawashiri, Cyrille Maugeais, Daniel J. RaderAbstract:New therapeutic approaches to the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) are needed. Plasma levels of high-density lipoprotein (HDL) Cholesterol are inversely associated with risk of ASCVD. Genes involved in the metabolism of HDL represent potential targets for the development of such therapies. Because HDL metabolism is a dynamic process, the effect of a specific HDL-oriented intervention on atherosclerosis cannot necessarily be predicted by its effect on the plasma HDL Cholesterol level. Based on available data in animal models, some gene products are candidates for pharmacologic upregulation, infusion, or overexpression, including apolipoprotein (apo)A-I, apoE, apoA-IV, lipoprotein lipase (LPL), ATP-binding cassette protein 1 (ABC1), lecithin Cholesterol acyltransferase (LCAT), and scavenger receptor B-I (SR-BI). In contrast, some gene products are potential candidates for inhibition, including apoA-II, cholesteryl ester transfer protein (CETP), and hepatic lipase. The next decade will witness the transition from preclinical studies to clinical trials of a variety of new therapies targeted toward HDL metabolism and atherosclerosis.
Robert S Meidell - One of the best experts on this subject based on the ideXlab platform.
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role of acyl coenzyme a Cholesterol acyltransferase 1 in the control of hepatic very low density lipoprotein secretion and low density lipoprotein receptor expression in the mouse and hamster
Journal of Biological Chemistry, 2000Co-Authors: David K Spady, Maureen N Willard, Robert S MeidellAbstract:Abstract Cholesteryl esters present in nascent very low density lipoproteins are generated in a reaction catalyzed by acyl CoA:Cholesterol acyltransferase (ACAT). To examine the effect of cholesteryl esters on the secretion of apoB-containing lipoproteins, we transiently overexpressed human (h) ACAT-1 in the livers of low density lipoprotein (LDL) receptor−/− mice using adenovirus-mediated gene transfer. Overexpression of hACAT-1 increased hepatic total and esterified Cholesterol but did not reduce hepatic free Cholesterol due to a compensatory increase in the rate of de novo Cholesterol synthesis. Overexpression of hACAT-1 markedly increased the plasma concentration and hepatic secretion of apoB-containing lipoproteins but had no effect on the clearance of very low density lipoprotein-apoB from plasma indicating that cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. ACAT activity has been implicated in the regulation of the LDL receptor pathway by dietary fatty acids. It has been hypothesized that unsaturated fatty acids, by enhancing ACAT activity, reduce the amount of free Cholesterol in a putative regulatory pool that feeds back on LDL receptor expression. We directly tested this hypothesis in hamsters by transiently overexpressing hACAT-1 in the liver. Enhanced Cholesterol esterification in the liver resulted in a compensatory increase inde novo Cholesterol synthesis but no induction of LDL receptor expression suggesting that fatty acids regulate LDL receptor expression via a mechanism independent of ACAT.
D C Anderson - One of the best experts on this subject based on the ideXlab platform.
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The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in type 1 diabetes associated with hyperCholesterolaemia or combined hyperlipidaemia.
Atherosclerosis, 1992Co-Authors: P H Winocour, P N Durrington, D Bhatagnar, M Ishola, M Mackness, S Arrol, D C AndersonAbstract:Lipoprotein composition was examined in type 1 diabetic subjects with hyperCholesterolaemia +/- hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hyperCholesterolaemia alone, bezafibrate significantly reduced the Cholesterol (particularly esterified Cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60-400) in comparison to the placebo group (P less than 0.05), and a trend towards a reduction in free and esterified Cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12-20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL Cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P less than 0.05). An additional significant reduction in small VLDL (Sf 20-60) free Cholesterol was recorded (P less than 0.05). Average reductions of large and small VLDL protein of 50-56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hyperCholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.
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The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in Type 1 diabetes associated with hyperCholesterolaemia or combined hyperlipidaemia
Atherosclerosis, 1992Co-Authors: P H Winocour, P N Durrington, D Bhatagnar, M Ishola, M Mackness, S Arrol, D C AndersonAbstract:Lipoprotein composition was examined in type 1 diabetic subjects with hyperCholesterolaemia ± hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hyperCholesterolaemia alone, bezafibrate significantly reduced the Cholesterol (particularly esterified Cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60–400) in comparison to the placebo group (P < 0.05), and a trend towards a reduction in free and esterified Cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12–20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL Cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P < 0.05). An additional significant reduction in small VLDL (Sf 20–60) free Cholesterol was recorded (P < 0.05). Average reductions of large and small VLDL protein of 50–56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hyperCholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.
Tatsuya Takano - One of the best experts on this subject based on the ideXlab platform.
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accumulation of oleate rich cholesteryl esters by acetyl ldl in macrophages in the presence of an acyl coa Cholesterol acyltransferase inhibitor sandoz 58 035
Biochemistry international, 1990Co-Authors: O Shimasaki, Chieko Mineo, Hiroomi Mowri, Shoji Ohkuma, Tatsuya TakanoAbstract:The mechanism through which cholesteryl esters rich in oleic acid accumulate in the cytoplasm was studied. The fatty acid composition of the cholesteryl esters in acetyl-LDL was high in linoleic acid, while that of cholesteryl ester inclusion bodies accumulated in the cytoplasm was high in oleic acid. This compositional change of fatty acids in cholesteryl esters occurred even in the presence of an acyl-CoA: Cholesterol acyltransferase (ACAT) inhibitor, Sandoz 58-035. These results suggest that oleate-rich cholesteryl esters accumulated in the cytoplasm, even though the reesterification in microsome was inhibited by an ACAT inhibitor.
David K Spady - One of the best experts on this subject based on the ideXlab platform.
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role of acyl coenzyme a Cholesterol acyltransferase 1 in the control of hepatic very low density lipoprotein secretion and low density lipoprotein receptor expression in the mouse and hamster
Journal of Biological Chemistry, 2000Co-Authors: David K Spady, Maureen N Willard, Robert S MeidellAbstract:Abstract Cholesteryl esters present in nascent very low density lipoproteins are generated in a reaction catalyzed by acyl CoA:Cholesterol acyltransferase (ACAT). To examine the effect of cholesteryl esters on the secretion of apoB-containing lipoproteins, we transiently overexpressed human (h) ACAT-1 in the livers of low density lipoprotein (LDL) receptor−/− mice using adenovirus-mediated gene transfer. Overexpression of hACAT-1 increased hepatic total and esterified Cholesterol but did not reduce hepatic free Cholesterol due to a compensatory increase in the rate of de novo Cholesterol synthesis. Overexpression of hACAT-1 markedly increased the plasma concentration and hepatic secretion of apoB-containing lipoproteins but had no effect on the clearance of very low density lipoprotein-apoB from plasma indicating that cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. ACAT activity has been implicated in the regulation of the LDL receptor pathway by dietary fatty acids. It has been hypothesized that unsaturated fatty acids, by enhancing ACAT activity, reduce the amount of free Cholesterol in a putative regulatory pool that feeds back on LDL receptor expression. We directly tested this hypothesis in hamsters by transiently overexpressing hACAT-1 in the liver. Enhanced Cholesterol esterification in the liver resulted in a compensatory increase inde novo Cholesterol synthesis but no induction of LDL receptor expression suggesting that fatty acids regulate LDL receptor expression via a mechanism independent of ACAT.