Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.

Mann, Christopher; Yen, Frances T.; Grant, Alison M.; Bihain, Bernard E.

doi:10.1172/jci115535

Cited by 323 publications

(175 citation statements)

References 27 publications

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“…4 -6 ' 9 ' 31 For instance, elevations in VLDL-TG may enhance the net mass transfer of CE out of HDL. 31 It is unlikely that this effect was operating in our study subjects because TG levels were similar in smokers and nonsmokers. PLTP is presumed to facilitate the transfer of phospholipids from TG-rich lipoproteins toward HDL during lipolysis.…”

Section: Discussionmentioning

confidence: 80%

Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men.

Dullaart

Hoogenberg

Dikkeschei

et al. 1994

Arterioscler Thromb

105

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The mechanisms responsible for the atherogenic lipoprotein changes associated with cigarette smoking are largely unknown. Lecithin: cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of plasma cholesterol and the transfer of cholesteryl ester from high-density lipoproteins (HDLs) toward very-low-and low-density lipoproteins (VLDLs+LDLs). Another transfer factor, phospholipid transfer protein (PLTP), recently has been shown to be involved in the interconversion of HDL particles in vitro, but its physiological function is not yet clear. We measured the activities of LCAT, CETP (as cholesteryl ester exchange activity), and PLTP using exogenous substrate assays as well as lipoprotein profiles in the plasma of 21 nonnolipidemic cigarette-smoking men (total plasma cholesterol below 6.5 mmol/L and trigh/ceride below 2.5 mmol/L) and 21 individually matched nonsmoking control subjects. HDL cholesterol, HDL cholesteryl ester, and plasma apolipoprotein A-I levels were lower in the smokers than in the control subjects (Ps.05 for all parameters). Median plasma CETP activity was 18% higher (P<.02) and median plasma PLTP activity was 8% higher (P<.05) in the smokers C igarette smoking is associated with higher levels of very-low-and low-density lipoprotein (VLDL+ LDL) cholesterol and lower levels of high-density lipoprotein (HDL) cholesterol. 1 Such unfavorable lipoprotein alterations can explain in part the increased risk of cardiovascular disease among smokers. 2 Of other factors involved in lipoprotein metabolism, lecithin:cholesterol acyltransferase (LCAT, EC 23.1.43) and cholesteryl ester transfer protein (CETP) play key roles in the esterification of cholesterol in plasma and the subsequent transfer of cholesteryl ester (CE) toward apolipoprotein (apo) B-containing lipoproteins. 3 -6 High levels of CETP activity have been previously documented in primary and secondary hyperlipidemia. 711 Furthermore, HDL cholesterol is extremely elevated in cases of familial CETP deficiency. 12 Apart from CETP, another lipid transfer factor, phospholipid transfer protein (PLTP), specifically catalyzes the transfer of phospholipids in plasma. 46 though its physiological function is not well defined, PLTP is involved in regulating HDL particle size in vitro. 14 The mechanisms responsible for the unfavorable lipoprotein levels in smokers still are not precisely understood. Previous studies did not demonstrate significant alterations in the plasma cholesterol esterification rate in smokers. 1516 CETP activity was found to be elevated in cigarette-smoking men with insulin-dependent diabetes mellitus, 17 but it is unknown whether such abnormalities are present in smoking subjects without other cardiovascular risk factors.We hypothesized that alterations in plasma lipid transfer protein activities could play a role in the development of unfavorable lipoprotein changes in smokers. In this case-control study we measured plasma CETP, PLTP, and LCAT activity in carefully...

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Section: Discussionmentioning

confidence: 80%

Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men.

Dullaart

Hoogenberg

Dikkeschei

et al. 1994

Arterioscler Thromb

105

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“…It has been suggested that CETP may be in excess in the plasma of normolipidemic subjects, such that cholesteryl ester transfer rates are determined by plasma triglyceride concentrations; by contrast, CETP may be limiting in hypertriglyceridemic patients, in which case, transfer rates may be determined by plasma CETP concentration. 53 The association between the Ϫ629 polymorphism and HDL-C could be, at least in part, the consequence of alterations in plasma CETP mass, especially in dyslipidemic individuals. The lack of correlation between CETP mass and HDL-C could reflect the contribution of metabolic and environmental factors to the modulation of HDL-C.…”

Section: Discussionmentioning

confidence: 99%

New Functional Promoter Polymorphism, CETP/−629, in Cholesteryl Ester Transfer Protein (CETP) Gene Related to CETP Mass and High Density Lipoprotein Cholesterol Levels

Dachet

Poirier

Cambien

et al. 2000

ATVB

169

128

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Abstract-A new polymorphism located at position Ϫ629 (CETP/Ϫ629A/C) in the promoter of the cholesteryl ester transfer protein (CETP) gene is described. The Ϫ629A allele was associated with lower CETP mass (PϽ0.0001) and higher high density lipoprotein cholesterol (PϽ0.001) than the C allele in a sample of 536 control subjects from the ECTIM study. Transfection studies in HepG2 cells with a luciferase expression vector incorporating a 777-bp fragment of the CETP promoter and containing either A or C at position Ϫ629 showed significantly lower luciferase activity with the promoter fragment of the A allele (Ϫ25%, PϽ0.05). By gel-shift assay, DNA-protein interactions were evaluated in nuclear extracts of HepG2 cells with the use of 2 probes (A or C probe) composed of 20 bp of the promoter sequence surrounding the polymorphic site. Two specific complexes of distinct migration rate were identified with the A and the C probe. Competition with an excess of oligonucleotide containing the Sp1 consensus binding site showed that a protein(s) of the Sp transcription factor family was implicated in complex formation with the A probe but not with the C probe. Incubation with specific antibodies indicated that Sp1 and Sp3 bound specifically to the A probe. We introduced mutations in the Ϫ629-Sp1 binding site to test its functionality and to define the characteristics of transcription factor binding. We showed, by gel-shift assay, that no nuclear proteins bound to the mutated sequence. Transient transfection of HepG2 cells revealed that the expression of the mutated fragment was significantly increased compared with that of the A promoter fragment (25%, PϽ0.05). The mutated fragment displayed the same activity as that of the C promoter. These results indicate that Sp1 and/or Sp3 repress CETP promoter activity, whereas nuclear factors binding the C allele are without effect on promoter expression. Key Words: cholesteryl ester transfer protein Ⅲ gene polymorphisms Ⅲ transcription factors Ⅲ ECTIM Ⅲ cardiovascular disease S everal prospective epidemiological studies have shown that elevated levels of HDL cholesterol (HDL-C) constitute an independent negative risk factor for coronary heart disease. 1 Cholesteryl ester transfer protein (CETP) plays a central role in the reverse transport of cholesterol from peripheral tissues to the liver and in the remodeling of plasma lipoproteins by promoting the transfer of cholesteryl esters from HDL to LDL and VLDL lipoproteins. 2,3 The critical role of CETP in lipoprotein metabolism is illustrated by the high levels of HDL-C observed in patients with genetic CETP deficiency. 4 In addition, elevated levels of CETP activity may contribute to an increased risk of coronary artery disease by reducing the cholesterol content of HDL relative to LDL and VLDL 5 and by promoting the formation of atherogenic, small, dense LDL in hyperlipidemic patients. 6 Several common polymorphisms have been described in the CETP gene, 7-10 most of which are associated with plasma CETP mass and HDL-C levels. 9,11,12 How...

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“…Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL. 22 5. Increase in HDL production and stimulation of reverse cholesterol transport.…”

Section: Mechanisms Of Action Of Fibratesmentioning

confidence: 99%

Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism

et al. 1998

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Abstract-Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-␣ form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase-mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the ␤-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression. (Circulation. 1998;98:2088-2093.)Key Words: apolipoproteins Ⅲ arteriosclerosis Ⅲ fibrates Ⅲ hypercholesterolemia Ⅲ hyperlipoproteinemia Ⅲ lipids Ⅲ PPAR A vast number of studies confirmed the intimate and causative relationships between dyslipidemias and coronary heart disease. Although hypercholesterolemia is an important underlying cause for coronary heart disease, other dyslipidemias, such as hypoalphalipoproteinemia (low plasma HDL) and hypertriglyceridemia, may be causative in a substantial number of cases. Fibrates are useful for the treatment of hypoalphalipoproteinemia with or without hypertriglyceridemia.1,2 The recommendation for the use of fibrates in certain types of dyslipidemia has gained additional support from a subgroup analysis of the Helsinki Heart Study, 3 which showed that the best preventive efficacy has been achieved in a subset of Ϸ10% of the study population who had a baseline LDL:HDL cholesterol ratio of Ͼ5 and a triglyceride level of 2.3 mmol/L. 4,5 Results from angiographic trials revealed that fibrates retard the progression of coronary atherosclerosis and decrease the number of coronary events. 6,7 Pharmacological Action of FibratesFibrates are generally effective in lowering elevated plasma triglycerides and cholesterol. The magnitude of lipid changes depends, however, on the patient's pretreatment lipoprotein status 8 as well as the relative potency of the fibrate used. 9 The most pronounced effects of fibrates are a decrease in plasma triglyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol (LDL-C) generally decrease in individuals with elevated baseline plasma concentrations, and HDL cholesterol (HDL-C) levels are u...

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Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.

Cited by 323 publications

References 27 publications

Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men.

Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men.

New Functional Promoter Polymorphism, CETP/−629, in Cholesteryl Ester Transfer Protein (CETP) Gene Related to CETP Mass and High Density Lipoprotein Cholesterol Levels

Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism

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