Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency

Sakai, Naohiko; Yamashita, Shizuya; Hirano, Ken‐ichi; Ishigami, Masato; Arai, T.; Kobayashi, Kaori; Funahashi, Tohru; Matsuzawa, Yūji

doi:10.1111/j.1365-2362.1995.tb01710.x

Cited by 58 publications

(29 citation statements)

References 53 publications

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“…The lipoprotein abnormalities in CETP deficiency are also characterized by the presence of polydisperse LDL enriched with triglycerides and large, CE-rich HDL particles. [11][12][13][14] These results indicated that CETP is involved in the regulation of plasma lipoproteins by modulating both the quantity and quality of each lipoprotein particle.…”

mentioning

confidence: 78%

Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

Nagano

Yamashita

Hirano

et al. 2001

ATVB

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Abstract-Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo)B-containing lipoproteins and plays a crucial role in reverse cholesterol transport, which is a major protective system against atherosclerosis. Genetic CETP deficiency is the most common cause of a marked hyperalphalipoproteinemia (HALP) in the Japanese, and various mutations have been identified in the coding region as well as in the exon/intron boundaries in the CETP gene. In the present study, we identified a novel mutation in the promoter region of the CETP gene. This mutation was a G-to-A substitution at the Ϫ69 nucleotide of the promoter region (Ϫ69 G3 A), corresponding to the second nucleotide of the PEA3/ETS binding site (CGGAA) located upstream of the putative TATA box. Four (2.0%) of 196 unrelated subjects with a marked HALP (HDL cholesterol Ն2.59 mmol/Lϭ100 mg/dL) were revealed to be heterozygous for the Ϫ69 G3 A mutation, and the allelic frequency of the mutant was 0.0102 in the subjects with a marked HALP. The subjects with the Ϫ69 G3 A mutation had low plasma CETP levels. Reporter gene assay showed that this mutation markedly reduced the transcriptional activities in HepG2 cells (8% of wild type). These results suggested that this mutation would be dominant negative. In conclusion, a novel Ϫ69 G3 A mutation in the CETP gene causes the decreased transcriptional activity leading to HALP. Key Words: cholesteryl ester transfer protein deficiency Ⅲ hyperalphalipoproteinemia Ⅲ mutation Ⅲ promoter Ⅲ PEA3/ETS binding site C holesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyzes the transfer of cholesteryl ester (CE) from HDL to apolipoprotein (apo) B-containing lipoproteins and is one of the major determinants of plasma HDL cholesterol levels. 1-3 Genetic CETP deficiency is the most common cause of hyperalphalipoproteinemia (HALP) in the Japanese. 4 -10 It has been demonstrated that a G-to-A substitution at the 5Ј splice donor site of intron 14 (Int14 ϩ1 G3 A) and a missense mutation of exon 15 (D442G) in the CETP gene are common mutations associated with HALP. These 2 mutations are relatively frequent in the Japanese population. 5,7,8,10 Patients with CETP deficiency have moderate hypercholesterolemia and markedly increased levels of HDL cholesterol. The lipoprotein abnormalities in CETP deficiency are also characterized by the presence of polydisperse LDL enriched with triglycerides and large, CE-rich HDL particles. 11-14 These results indicated that CETP is involved in the regulation of plasma lipoproteins by modulating both the quantity and quality of each lipoprotein particle.In addition, CETP plays an important role in reverse cholesterol transport from peripheral tissues to the liver. 15,16 Recently, CETP deficiency has been thought to be a proatherogenic state because of the crucial role of CETP in reverse cholesterol transport despite high HDL cholesterol levels. The study of the Omagari area in Japan, where the Int14 ϩ1 G3 A mutation is extremely frequent...

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confidence: 78%

Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

Nagano

Yamashita

Hirano

et al. 2001

ATVB

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“…This CETP effect could be related to its capacity to modify LDL's affinity for its specific receptors. Accordingly, Sakai et al (64) reported that CETP-deficient patients presented LDL particles with decreased affinity for LDL receptors. In another work (65), we showed that CETP transfers CE from OxLDL to HDL more efficiently than from native LDL.…”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice

Casquero

Berti

Salerno

et al. 2006

Journal of Lipid Research

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In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and dietinduced atherosclerosis. CETP transgenic mice and nontransgenic (nTg) littermates were studied 4 weeks after bilateral orchidectomy or sham operation. Castrated mice had an increase in the LDL fraction (136% for CETP and 179% for nTg mice), whereas the HDL fraction was reduced (230% for CETP and 211% for nTg mice). Castrated mice presented 1.7-fold higher titers of anti-oxidized LDL (Ox-LDL) antibodies than sham-operated controls. Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration. Kinetic studies showed no differences in VLDL secretion rate, VLDL-LDL conversion rate, or number of LDL and HDL receptors. Competition experiments showed lower affinity of LDL from castrated mice for tissue receptors. Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions. The expression of CETP led to a milder increase of apoB-LPs and reduced atherosclerotic lesion size in testosterone-deficient mice. Gender differences in coronary artery disease (CAD) risk observed during the reproductive life period have been attributed to an attenuating effect of estrogen on atherogenesis (1, 2) and/or to a proatherogenic action of androgens (3, 4). However, the unexpected outcomes from the Women's Health Initiative and Heart and Estrogen Replacement Study trials (5, 6) and other controversies about the role of androgens (7) necessitate further investigation of the role of sex steroids, especially in sexmatched individuals. Androgen's effects on lipoprotein metabolism and risk of atherosclerosis are not unequivocal (7,8). Increased endogenous serum testosterone in men has been associated with a favorable lipid profile (9, 10), and low endogenous levels of testosterone have been associated with an atherogenic lipid profile (11, 12) and CAD (13,14). However, other studies have not found such relationships (15-18). Aromatization of testosterone into 17b-estradiol seems to be an important determinant of the beneficial effects of androgens observed in men (19,20) and mice (21,22). On the other hand, increasing endogenous androgen levels in women (23, 24), androgenic supplementation in men (3), in women (25), and in female animals (26,27), and nonmedical use of androgenic anabolic steroids (4,28,29) are associated with increased risk factors for atherosclerotic diseases.Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein B-containing lipoproteins (apoB-LPs) in exchange for triglycerides (TGs), thus remodeling HDL composition in the plasma of sev...

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“…In addition, Sakai et al have reported that the affinity of abnormal low-density lipoprotein (LDL) from CETP-deficient patients for the LDL receptor was largely decreased. 15 The delay in LDL catabolism is thought to result in increased opportunity for oxidation of LDL, and the change in LDL observed in patients with CETP deficiency could thus be atherogenic.…”

Section: Discussionmentioning

confidence: 99%

Effort Angina in a Middle-Aged Woman With Abnormally High Levels of Serum High-Density Lipoprotein Cholesterol A Case of Cholesteryl-Ester Transfer Protein Deficiency

Nagano

Nakamura

Kobayashi

et al. 2005

Circ J

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erum concentrations of high-density lipoprotein cholesterol (HDL-C) are inversely correlated with the prevalence of coronary artery disease. The favorable effect of high-density lipoprotein (HDL) essentially depends on the activity of cholesteryl ester transfer protein (CETP). 1 In fact, CETP catalyzes the transfer of cholesteryl esters from HDL to other lipoproteins, and is a key participant in the reverse transport of cholesterol from the periphery to the liver. 2 Several types of genetic CETP deficiency are prevalent in certain ethnic populations including those from Germany, Finland, and Japan. [3][4][5][6] It has been suggested that in populations with CETP gene mutations, the overall prevalence of coronary artery disease is higher than among populations without these mutations, 4 although the mutations are associated with increased serum concentrations of HDL-C. In fact, in vitro studies have shown that in CETP deficiency large cholesteryl ester-rich HDL particles are defective in cholesterol efflux. It might therefore be hypothesized that low concentrations of CETP appear to be an independent risk factor for atherosclerotic cardiovascular diseases. Although one previous report described a few cases of hyperHDL2 cholesterolemia complicating coronary artery disease and the effectiveness of probucol in the treatment of hypercholesterolemia, 7 few case reports examining genetic CETP deficiency have provided detailed data Circulation Journal Vol.69, May 2005 on lipid concentrations and the therapeutic effects of antilipidemic agents. We report a case of angina pectoris in a middle-aged woman who exhibited a markedly high serum HDL-C concentration (>200 mg/dl) without any other clas- A 54-year-old female was admitted to hospital complaining of oppressive anterior chest pain during exercise. Treadmill exercise ECG testing showed significant ischemic ECG changes, and electron-beam computed tomography demonstrated patchy calcifications in the coronary artery. Coronary angiography revealed a significant stenotic lesion of the right coronary artery. On routine investigations, no classical coronary risk factors were found, although a very high concentration (209 mg/dl) of high-density lipoprotein cholesterol (HDL-C) was detected. The serum concentration of cholesteryl-ester transfer protein (CETP), which plays a central role in the reverse cholesterol transport system, was measured and found to be less than the measurable minimum. The patient showed one of the typical genetic CETP mutations (intone 14 splicing defect), and her lipid profile was improved by administration of probucol for 3 months. A very high concentration of HDL-C with a defect of CETP activity may be a specific biochemical indicator pointing to an increased risk of premature coronary artery disease, and the lipid profile can be improved by use of lipid-lowering drugs. CASE REPORTS

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Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency

Cited by 58 publications

References 53 publications

Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

Point Mutation (−69 G→A) in the Promoter Region of Cholesteryl Ester Transfer Protein Gene in Japanese Hyperalphalipoproteinemic Subjects

Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice

Effort Angina in a Middle-Aged Woman With Abnormally High Levels of Serum High-Density Lipoprotein Cholesterol A Case of Cholesteryl-Ester Transfer Protein Deficiency

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