Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia

Yamashita, Shizuya; Maruyama, Takao; Hirano, Ken‐ichi; Sakai, Naohiko; Nakajima, Noriaki; Matsuzawa, Yūji

doi:10.1016/s0021-9150(00)00574-8

Cited by 89 publications

(56 citation statements)

References 114 publications

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“…In addition, there were no significant differences in the level of inflammation (assessed as plasma CRP level) and plasma activities of CETP and phospholipid-transfer protein between the groups (data not shown). HL activity was significantly decreased in HALP subjects as compared with controls (2.44Ϯ1.04 versus 3.93Ϯ1.46 mol free fatty acids/mL per hour; Pϭ0.02); decreased HL activity may therefore be responsible for HALP in our study population, consistent with the classification of Yamashita et al 2 …”

Section: Subjectssupporting

confidence: 89%

“…1 Marked elevation in HDL-C levels is typical of hyperalphalipoproteinemia (HALP), which is characterized by plasma levels of HDL-C above the 90th percentile for an age-and sex-matched general population. 2,3 Primary HALP can arise from genetic deficiency of plasma cholesteryl ester transfer protein (CETP) and/or hepatic lipase (HL), as well as from increased production of apolipoprotein A-I (apoA-I), a major HDL apolipoprotein; 2 equally, however, HALP may be of unknown etiology. HALP involves modification of the physicochemical properties, metabolism, and function of HDL; for example, large CE-rich HDL2 particles that accumulate in familial CETP deficiency possess diminished capacity for cholesterol efflux from macrophages.…”

mentioning

confidence: 99%

“…HALP involves modification of the physicochemical properties, metabolism, and function of HDL; for example, large CE-rich HDL2 particles that accumulate in familial CETP deficiency possess diminished capacity for cholesterol efflux from macrophages. 2 In a transgenic mouse model of HALP overexpressing human lecithin-cholesterol acyltransferase (LCAT), dysfunctional HDL exhibits diminished capacity for reversecholesterol transport (RCT). 4 The antiatherogenic actions of HDL reflect functional biological properties of HDL particle subpopulations rather than absolute plasma levels of HDL-C. 5 A spectrum of antiatherogenic activities is associated with HDL particles, which include the capacity to transport cholesterol from arterial wall cells to the liver in the RCT pathway and to exert antiinflammatory and antioxidative activities.…”

mentioning

confidence: 99%

“…The intravascular metabolism and particle heterogeneity of HDL are altered in HALP. 2 The impact of such modification on the antioxidative activities of HDL remains, however, to be established. Therefore, we evaluated the capacity of distinct HDL subfractions (HDL2b, 2a, 3a, 3b, and 3c) from normocholesterolemic HALP subjects to protect LDL from oxidation.…”

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confidence: 99%

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Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties

Kontush

Faria

Chantepie

et al. 2004

ATVB

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Objective-Hyperalphalipoproteinemia (HALP) is characterized by elevated plasma levels of high-density lipoprotein (HDL) particles with altered composition, metabolism, and function. The impact of such modification on antioxidative activities of HDL subfractions is indeterminate. Methods and Results-Gradient fractionation revealed that buoyant HDL2b and 2a and small dense HDL3b and 3c levels were elevated up to 2.0-fold in HALP subjects (nϭ9; mean plasma HDL cholesterol, 79 mg/dL) with low hepatic lipase activity. HDL2a, 3a, 3b, and 3c displayed lower specific antioxidative activity (sAA) during low-density lipoprotein (LDL) oxidation (Ϫ15% to Ϫ86%, on a unit particle mass basis) than their normolipidemic counterparts (nϭ13). LDL oxidation was delayed by control HDL3a, 3b, and 3c (up to Ϫ79%) but specifically by HDL3c (Ϫ54%) in HALP. Paraoxonase activity was deficient in all HALP HDL subfractions. Paraoxonase, PAF-AH, and LCAT activities together accounted for Ϸ50% of variation in sAA. Abnormal chemical composition of HDL3b and 3c (cholesterol-deficient, triglyceride-enriched) in HALP was associated with impaired sAA. Systemic oxidative stress (as plasma 8-isoprostanes) tended to be elevated (1.5-fold) in HALP and negatively correlated with sAA (as TBARS). Conclusions-Intrinsic

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Section: Subjectssupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties

Kontush

Faria

Chantepie

et al. 2004

ATVB

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“…[9][10][11][12][13][14][15][16][17][18][19][20] CETP deficiency associated with elevated HDL-C may, paradoxically, increase the risk for CHD in certain genotype/phenotype constellations. 21 However, in a large sib-pair linkage analysis, no relationship between allelic variation at the CETP locus and plasma HDL-C levels was detected, despite an association between CETP gene variation and plasma CETP concentrations. 22 One explanation for these conflicting data may be that analyses based on associations between individual SNPs and clinical phenotypes do not reflect the subtle interactions of many individual SNPs within the CETP gene.…”

Section: Introductionmentioning

confidence: 94%

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Winkelmann¹,

Hoffmann

Nauck

et al. 2003

Pharmacogenomics J

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Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P¼0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P¼0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins. The Pharmacogenomics Journal (2003) 3, 284-296, doi:10.1038/sj.tpj.6500195Keywords: cholesteryl ester transfer protein; HDL-cholesterol; triglycerides; haplotype; single nucleotide polymorphism; statin INTRODUCTION Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and plays a central role in high-density lipoprotein (HDL) metabolism. CETP transfers cholesteryl esters associated with HDL to triglyceride-rich lipoproteins, facilitating the clearance of cholesteryl esters from plasma. 1 Although the potential contribution of CETP to reverse cholesterol transport suggests an antiatherogenic mode of action, knowledge of the physiologic role of CETP in lipoprotein metabolism remains incomplete. The overall effect of CETP on atherogenesis may vary depending on both metabolic context and molecular variation in the CETP gene. 2 Investigations of associations between genetic variants in CETP and cardiovascular phenotypes are numerous, but often conflicting in their findings. The Taq1B polymorphism of the CETP gene has been associated with plasma levels of CETP and HDL cholesterol (HDL-C) and with the risk of coronary heart disease (CHD). 3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the

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Abnormal Metabolism

2011

High‐Density Lipoproteins

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Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia

Cited by 89 publications

References 114 publications

Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties

Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Abnormal Metabolism

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