Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency

Koizumi, Junji; Inazu, Akihiro; Yagi, Kunimasa; Koizumi, Ichiro; Uno, Yusuke; Kajinami, Kouji; Miyamoto, Susumu; Moulin, Philippe; Tall, Alan R.; Mabuchi, Hiroshi

doi:10.1016/0021-9150(91)90114-i

Cited by 91 publications

(39 citation statements)

References 28 publications

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“…However, these individuals had triglyceride levels < 400 mg/dl, which may not have been high enough to observe this relationship. Finally, although this was not addressed in the current study, recently another group created CETP transgenic mice and found that decreased HDL-C was accompanied by increased VLDL-C and LDL-C levels, as expected from studies in humans (35)(36)(37).…”

Section: Discussionsupporting

confidence: 49%

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Hayek¹,

Azrolan²,

Verdery³

et al. 1993

J. Clin. Invest.

127

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Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved. (J.

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Section: Discussionsupporting

confidence: 49%

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Hayek¹,

Azrolan²,

Verdery³

et al. 1993

J. Clin. Invest.

127

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“…This was in good agreement with the characteristic increase of the esterified cholesterol: trigh/ceride ratio observed in the HDL from subjects with low CETP activity. 45 In the present study, LCAT activity correlated negatively with total cholesterol, HDL-C, and VLDL+LDL-C concentrations. Whereas these observations confirmed some of the data previously published, 4647 they disagreed with others.…”

Section: Effect Of Incubation Of Total Plasma On Ldl Patterns To Invsupporting

confidence: 50%

Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in normolipidemic subjects.

Lagrost¹,

Gandjini²,

Athias³

et al. 1993

Arterioscler Thromb

115

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The relations of cholesteryl ester transfer protein (CETP) activity to the distribution of low density lipoproteins (LDLs) and high density lipoproteins (HDLs) were investigated in fasting plasma samples from 27 normolipidemic subjects. LDL and HDL subtractions were separated by electrophoresis on 20-160 g/L and 40-300 g/L polyacrylamide gradient gels, respectively. Subjects were subdivided into two groups according to their LDL pattern. Monodisperse patterns were characterized by the presence of a single LDL band, whereas polydisperse patterns were characterized by the presence of several LDL bands of different sizes. To investigate the influence of lipid transfers on LDL patterns, total plasma was incubated at 37°C in the absence of lecithin: cholesterol acyltransferase (LCAT) activity. The incubation induced a progressive transformation of polydisperse patterns into monodisperse patterns. Under the same conditions, initially monodisperse patterns remained unchanged. Measurements of the rate of radiolabeled cholesteryl esters transferred from HDL 3 s to very low density lipoproteins (VLDLs) and LDLs revealed that subjects with a monodisperse LDL pattern presented a significantly higher plasma CETP activity than subjects with a polydisperse LDL pattern (301±85%/hr per milliliter versus 216±47%/hr per milliliter, respectively; p<0.02). In addition, when total plasma was incubated for 24 hours at 37°C in the absence of LCAT activity, the relative mass of cholesteryl esters transferred from

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“…In familial hypercholesterolemia, HDL levels of triglyceride are elevated and the cholesteryl ester/triglyceride ratio is reduced ( 120,121 ), refl ecting accelerated cholesteryl ester transfer from LDL and HDL to triglyceride-rich lipoproteins as a result of increased concentrations and abnormal properties of plasma VLDL1 ( 120,122,123 ). By contrast, attenuation of cholesteryl ester transfer from LDL and HDL to triglyceride-rich lipoproteins, as observed in plasma of subjects with heterozygous CETP defi ciency, results in elevated HDL cholesteryl ester content and reduced content of triglyceride ( 124 ).…”

Section: Vasodilatory Activitymentioning

confidence: 92%

Unraveling the complexities of the HDL lipidome

Kontush

Lhomme

Chapman

2013

Journal of Lipid Research

316

247

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This article is available online at http://www.jlr.org For many years, HDL lipids were predominantly characterized in terms of the content of their major classes, notably phospholipids, unesterifi ed (free) sterols (predominantly cholesterol), cholesteryl esters, and triglycerides. Cholesterol is the most characteristic component of the HDL lipidome as, in the form of HDL-cholesterol, it represents a major independent negative risk factor for cardiovascular disease (see other reviews in this Thematic Series). It is not cholesterol, however, but phospholipids that quantitatively predominate in the HDL lipidome, accounting, together with sphingomyelin (SM), for 40-60 wt% of total lipid, with lesser proportions of cholesteryl esters (30-40%), triglycerides (5-12%), and free cholesterol (5-10%). Structurally, individual HDL lipid classes fulfi ll distinct functions; phospholipids constitute the surface lipid monolayer of HDL, whereas cholesteryl esters and triglycerides form the hydrophobic lipid core. Unesterifi ed sterols are predominantly located to the surface monolayer, partially penetrating the core.Recent technological advances in mass spectrometry (MS) have enabled application of this powerful technique to provide a detailed identifi cation and quantifi cation of individual molecular species of lipids in the framework of the fi eld known as lipidomics. Application of this approach to plasma lipoproteins has revealed complex profi les consisting of hundreds of molecular lipid species that have been quantifi ed in major lipoprotein classes, including HDL (reviewed in Refs. 1-3 High density lipoproteins (HDL) are small, dense, protein-rich particles compared with other plasma lipoprotein classes. Despite the elevated abundance of multiple structural and functional proteins in HDL particles (see other reviews in this Thematic Series), roughly half of total HDL mass is accounted for by lipid components.

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Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency

Cited by 91 publications

References 28 publications

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in normolipidemic subjects.

Unraveling the complexities of the HDL lipidome

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