Objective-Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results-Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2 H 3 )-L-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in ␣1-migrating HDL in the atorvastatin (136%; PϽ0.001) and nonatorvastatin (153%; PϽ0.01) cohorts, whereas an increase of 382% (PϽ0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8Ϯ15% in the atorvastatin cohort (Pϭ0.16) and by 16Ϯ7% (PϽ0.0001) and 34Ϯ8% (PϽ0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with torcetrapib reducing HDL apoA-I FCR by 7% (Pϭ0.10) in the atorvastatin cohort, by 8% (PϽ0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% (PϽ0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion. Conclusions-These data indicate that partial inhibition of CETP via torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within ␣1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) pidemiologic studies have consistently demonstrated that plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are inversely correlated with the incidence of coronary heart disease (CHD). 1-3 Clinical trial results indicate that even modest increases in HDL cholesterol (HDL-C) concentrations can significantly reduce CHD risk. 4 -5 However, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, have only modest effects on HDL-C levels, raising them on average by 5% to 10%. 6 Although fibrates and niacin can raise HDL-C levels, the increases in HDL-C are rarely Ͼ25%, and niacin is often not well tolerated.Among the alternative HDL-raising strategies actively being explored is cholesteryl ester transfer protein (CETP) inhibition. 7 CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters (CEs) from HDL to apoBcontaining lipoproteins. 8,9 Humans with CETP deficiency attributab...

Objectives-Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. Methods and Results-We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Conclusion-Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48. Key Words: apolipoprotein Ⅲ high-density lipoprotein Ⅲ kinetics Ⅲ lipid-lowering medications Ⅲ triglyceride T he cholesterol-lowering effect of the vitamin nicotinic acid, or niacin, was first reported by Altschul et al 1 more than 50 years ago. Since then, treatment with pharmacological doses of niacin has been found to significantly lower the risk of coronary heart disease (CHD). 2,3 Several trials have also tested the effect of niacin in combination with other lipid-lowering medications on CHD risk, overall showing a beneficial effect. 4 -6 Niacin primarily decreases plasma triglyceride (TG) levels and very low-density lipoprotein (VLDL) cholesterol (C) levels and increases plasma highdensity lipoprotein (HDL)-C levels. 2,7 It has been hypothesized that the reduction in TG and VLDL-C is mediated by the niacin-associated inhibition of free-fatty acid (FFA) release from the adipose tissue, which may lead to reduced substrate availability for TG synthesis and secretion in hepatic cells. 8 However, a study conducted in 1 hypertriglyceridemic subject showed faster clearance of autologous 125 Ilabeled VLDL after niacin treatment. 9 Niacin is one of the most potent HDL-C-raising agents currently available. Two previous studies have attempted to elucidate the effect of niacin on HDL metabolism in young normocholesterolemic subjects. 10,11 The first study was conducted in 2 subjects and found an increase in HDL-C levels associated with a slower HDL catabolism with niacin. 10 The second study, in 5 young healthy subjects, found a significant increase in plasma HDL-C and apolipoprotein (apo) A-I levels with niacin withou...

Progress in our understanding of the composition and metabolism of LDL subfractions strengthens the association between sdLDL and CHD risk.

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebocontrolled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100-and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.-Lamon-Fava, S.,

Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease.

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...

Low serum high density lipoprotein cholesterol level (HDL-C) < 40 mg/dL in men and < 50 mg/dL in women are a significant independent risk factor for cardiovascular disease (CVD), and are often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (< 20 mg/dL) in the absence of secondary causes are much less common (< 1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with Apo A-I Deficiency, ApoA-I Variants, Tangier Disease, Familial Lecithin:Cholesteryl Ester Acyltransferase Deficiency, and Fish Eye Disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.

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