Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion

Brousseau, Margaret E.; Diffenderfer, Margaret R.; Millar, John S.; Nartsupha, Chorthip; Asztalos, Bela F.; Welty, Francine K.; Wolfe, Megan L.; Rudling, Mats; Björkhem, Ingemar; Angelin, Bo; Mancuso, James P.; Digenio, Andrés; Rader, Daniel J.; Schaefer, Ernst J.

doi:10.1161/01.atv.0000161928.16334.dd

Cited by 221 publications

(163 citation statements)

References 53 publications

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“…A unique lipoprotein particle, LpAI:AII:E, with attenuated catabolism relative to LpAI, is present in patients with CETP deficiency and markedly increased plasma HDL cholesterol concentrations (127,128 ). Decreased catabolism of LpAI and LpAI:AII with increased HDL cholesterol concentrations has also been reported in patients treated with CETP inhibitors (52 ). Decreased plasma levels of LpAI and LpAI:AII are seen in hypertriglyeridemic patients because of increased catabolism of triglyceride-enriched LpAI and LpAI:AII (129,130 ).…”

Section: Apo Ai and Apo Ai:aii Particlesmentioning

confidence: 99%

“…Large ␣-1 particles increase with weight loss, niacin, certain statins (atorvastatin, rosuvastatin), and CETP inhibitors (52)(53)(54)(55)(56)(57). Increasing the concentrations of apo AI in ␣-1 HDL to Ͼ200 mg/L (0.52 mmol/L) with a simvastatin/niacin combination has been associated with lack of progression and in some individuals with regression of coronary atherosclerosis (51 ).…”

Section: -D Gel Electrophoresismentioning

confidence: 99%

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HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

et al. 2011

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BACKGROUND A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. CONTENT In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux. SUMMARY We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.

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Section: Apo Ai and Apo Ai:aii Particlesmentioning

confidence: 99%

Section: -D Gel Electrophoresismentioning

confidence: 99%

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

et al. 2011

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“…Purifi ed HDL, but not LDL, signifi cantly enhanced inactivation of factor Va by activated protein C (APC) and protein S (69). HDL has also been shown to scavenge anionic phospholipids, pro-apoA-I or reconstituted HDL (rHDL; apoA-I purifi ed from human blood, reconstituted with phospholipids) was reported to result in an increase of sterol excretion (35,36) , but CETP inhibition (which blocks the exchange of cholesterol from HDL to LDL, resulting in a marked HDL-C increase as well as an LDL-C decrease) had no effect (37). Thus, human studies have only provided little evidence that HDL-C levels correlate with fecal cholesterol output.…”

Section: Other Potentially Atheroprotective Propertiesmentioning

confidence: 99%

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Vergeer

Holleboom

Kastelein

et al. 2010

Journal of Lipid Research

200

122

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This article is available online at http://www.jlr.org the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. EPIDEMIOLOGYA low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2-3% decreased CVD risk (3). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated lowdensity lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in signifi cant reductions of cardiovascular mortality and morbidity (4, 5) . It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk refl ect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6, 7). This is related to the fact that HDL-C levels are infl uenced by many different variables that also affect CVD risk: 1 ) Men have on average lower HDL-C levels than women (8). (1) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important fi ndings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to

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“…A detailed description of the study design, depicted in Figure 1, has been reported previously. 8,9 All subjects received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for an additional 4 weeks. Six subjects from the nonatorvastatin group also participated in a third phase, in which they received 120 mg torcetrapib twice daily for 4 weeks.…”

Section: Experimental Designmentioning

confidence: 99%

“…We reported previously that torcetrapib slowed the rate of clearance of apoA-I in plasma. 9 Here, we report the effects of torcetrapib on the metabolism of VLDL, intermediate-density lipoprotein (IDL), and LDL apoB100 in humans.…”

mentioning

confidence: 99%

Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

Millar

Brousseau²,

Diffenderfer³

et al. 2006

ATVB

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Objective-Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Methods and Results-Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. Conclusions-These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100. Key Words: very low-density lipoproteins Ⅲ triglyceride Ⅲ low-density lipoproteins Ⅲ cholesteryl ester transfer protein Ⅲ CETP inhibition Ⅲ lipoprotein kinetics A n elevated level of plasma cholesterol is a major risk factor for the development of cardiovascular disease. 1 Current treatments to reduce plasma cholesterol levels include diet, exercise, and treatment with cholesterol-lowering medications. 1 Recently, a new class of drug designed to increase high-density lipoprotein (HDL) cholesterol levels through the inhibition of cholesteryl ester transfer protein (CETP) has been developed. 2 CETP mediates the bidirectional exchange of cholesteryl ester and triglyceride between HDL and the apolipoprotein B (apoB)-containing lipoproteins, as well as among the different classes of apoBcontaining lipoproteins. The main result of CETP activity is net transfer of cholesteryl ester from HDL to very lowdensity lipoproteins (VLDLs) and net transfer of triglyceride from VLDL to HDL. Thus, CETP provides a link between the metabolism of apoB-containing lipoproteins and HDL. Expression of CETP in mice, 3 which normally lack CETP, or manipulation of CETP activity in other animals that express CETP 4,5 changes the plasma concentration of apoBcontaining lipoproteins in addition to expected changes in HDL chol...

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Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion

Cited by 221 publications

References 53 publications

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

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