GC × GC-MS analysis and hypolipidemic effects of polyphenol extracts from Shanxi-aged vinegar in rats under a high fat diet.

Oxidative stress, inflammation and gut microbiota disorders can be induced by long-term high-fat diets (HFD). In order to confirm that polyphenols can improve these symptoms, polyphenols from Shanxi-aged vinegar (SAVEP) were extracted, and the components were detected by Comprehensive two-dimensional gas chromatography mass spectrometry (GC × GC-MS). 41 polyphenols include 18 phenolic acids and 17 polyphenols, which have not been reported. The mechanism of SAVEP on oxidative stress and inflammatory stress induced by HFD in rats and its regulating effect on intestinal flora disorder were studied. The results showed that SAVEP could significantly improve the lipid, inflammatory stress and oxidative stress related indicators compared with the Model group ("Model" refers to the group that successfully constructed a hyperlipidemia model by feeding HFD without any drugs or SAVEP in subsequent experiments.). In addition, SAVEP decreased the Firmicutes/Bacteroidetes ratio compared with the Model group, and elevated the relative abundance of beneficial bacteria. Conclusively, SAVEP can alleviate the oxidative stress and inflammatory stress caused by HFD, improving intestinal microbial disorders. The Spearman's correlation analysis revealed that Desulfovibrio, Lactobacillus and Akkermansia were correlated negatively with all of the inflammatory indicators, whereas Ruminococcus was the opposite. These results suggest that SAVEP may be a novel strategy against oxidative stress and inflammation, restoring the normal microbial community ecology of the gut and the treatment of metabolic syndromes.

Accelerated atherosclerosis, hyperlipoproteinemia and insulin resistance in long-term survivors of Hodgkin lymphoma during childhood and adolescence.

Long-term survivors of Hodgkin lymphoma during childhood or adolescence (HL survivors) are at high risk of developing treatment-related late cardiovascular sequelae. In our study we evaluated the presence of modifiable cardiovascular risk factors (hypertension, hyperlipoproteinemia, hyperinsulinemia, obesity), endothelial and inflammatory markers (E-selectin, PAI-1, hs-CRP) and atherosclerotic changes in the common carotid arteries. Assessment was performed in 80 young adult Hodgkin lymphoma long-term survivors at more than 10 years after the potentially cardiovascular toxic anticancer treatment (median age at evaluation 34.7 years; range 24.1-40.9 years). The HL survivors were compared with 83 age- and gender-matched healthy volunteers. The HL survivors showed unfavorable lipid profiles compared to those of healthy controls: triglycerides (p=0.01), total cholesterol (p=0.0004), low density lipoprotein cholesterol (p=0.005). In HL survivors, we found a higher prevalence of hypertension (p=0.004) and insulin resistance - HOMA-IR (p=0.0002). Ultrasonographic examination of both common carotid arteries revealed a higher prevalence of atherosclerotic plaques (p=0.0009) and higher carotid intima-media thickness (p<0.0001) in HL survivors. Markers of oxidative stress (advanced oxidation protein products, oxidized low-density lipoprotein), inflammation (hs-CRP) and endothelial dysfunction (E-selectin, PAI-1) were also higher in HL survivors (p<0.0001, p=0.0002, p=0.0031, p=0.0087, p=0.004, respectively). Adult survivors of Hodgkin lymphoma during childhood and adolescence need closer follow-up with screening of metabolic syndrome components, unfavorable lifestyle factors and early management of these risk factors.

Persistent High Non-High-Density Lipoprotein Cholesterol in Early Childhood: A Latent Class Growth Model Analysis.

OBJECTIVES: To examine patterns of non-high-density lipoprotein (HDL) cholesterol in early childhood and identify factors associated with persistent high non-HDL cholesterol in healthy urban children. STUDY DESIGN: We identified all children enrolled in a primary care practice-based research network called TARGet Kids! (The Applied Research Group for Kids) with ≥3 laboratory measurements of non-HDL cholesterol. Latent class growth model analysis was performed to identify distinct trajectory groups for non-HDL cholesterol. Trajectory groups were then categorized into "normal" vs "persistent-high" non-HDL cholesterol based on guideline cut-off values and logistic regression was completed to examine the association between trajectory group and the presence of anthropometric and cardiometabolic risk factors. RESULTS: A total of 608 children met inclusion criteria for the trajectory analysis (median age at enrolment = 18.3, IQR = 27.9 months). Four trajectory groups were identified with 2 groups (n = 451) categorized as normal non-HDL cholesterol and 2 groups (n = 157) as persistent high non-HDL cholesterol. Family history of high cholesterol (OR 2.04, 95% CI 1.27-3.28) was associated significantly with persistent high non-HDL cholesterol, whereas East/Southeast Asian vs European ethnicity (OR 0.33, 95% CI 0.14-0.78), longer breastfeeding duration (OR 0.96, 95% CI 0.93-1.00), and greater birth weight (OR 0.69, 95% CI 0.48-1.00) were associated with lower odds of persistent high non-HDL cholesterol. CONCLUSIONS: Patterns of non-HDL cholesterol are identified during early childhood, and family history of high cholesterol was associated most strongly with persistent high non-HDL cholesterol. Future research should inform the development of a clinical prediction tool for lipids in early childhood to identify children who may benefit from interventions to promote cardiovascular health.

Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss.

The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol, and LDL; increased HDL/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1-14 or 8-14 weeks decreased HFD-induced liver and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10(-7)∼10(-5) M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3',5'-cyclic monophosphate (cGMP) antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL and restored oxidized LDL-induced PKA expresion. Unlike simvastatin, KMUP-1 could not inhibit (14)C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight.

Isolated midbrain ischemic infarct in association with hyperlipoproteinemia (a): a report of 2 adolescent patients.

Arterial ischemic strokes (AIS) localized solely to the midbrain are extremely uncommon in the pediatric population. Elevated lipoprotein (a), which promotes atherosclerosis and a prothrombotic state, has been associated with increased risk of AIS in children and adults. Here we describe a 17-year-old boy and a 15-year-old girl who presented with internuclear ophthalmoplegia secondary to an isolated midbrain AIS. Evaluation for risk factors for AIS in these otherwise healthy adolescents identified hyperlipoproteinemia (a) in combination with other potential prothrombotic conditions suggesting that hypercoagulable states such as hyperlipoproteinemia (a) may have contributed to development of small-vessel arteriopathy and localized AIS.

Low birthweight and elevated levels of lipoprotein(a) in prepubertal children.

AIM: To evaluate whether healthy prepubertal children with low birthweight (LBW) exhibited higher serum levels of lipoprotein(a) (Lp(a)) than did those with normal birthweight (NBW). METHODS: A total of 350 healthy children aged 6 to 9 years and in Tanner stage 1 were enrolled in a community-based cross-sectional study. Family history of hypertension, diabetes or cardiovascular disease (CVD) in parents and grandparents; active smoking; a diagnosis of acute or chronic illness; and intake of vitamins or nutritional supplements were exclusion criteria. The cut-off point for Lp(a) was 0.79 µmol/L. RESULTS: LBW was identified in 51 (14.6%) children. In total, 42 (12.0%) children had elevated Lp(a) levels, with 25 (49.0%) and 17 (5.7%) in the LBW and NBW groups, respectively (P < 0.0005). None of the children had adverse cardiovascular outcomes. Average body mass index (BMI) (17.1 ± 3.3 and 18.8 ± 3.9, P = 0.001), glucose levels (4.5 ± 0.5 and 4.8 ± 0.4 mmol/L, P = 0.007), insulin levels (67.4 ± 45.1 and 86.1 ± 54.9 pmol/L, P = 0.02), and Lp(a) levels (0.52 ± 0.21 and 1.40 ± 0.49 µmol/L, P < 0.0005) were higher in the children with LBW than in the children with NBW. A multivariate analysis adjusted by age, sex, raw BMI, BMI standard deviation score and insulin level showed a significant association between LBW and elevated levels of Lp(a) (odds ratio 8.02, 95% confidence interval 7.3-21.3; P < 0.0005). CONCLUSIONS: LBW was shown to be strongly associated with elevated serum levels of Lp(a).

Changes in low-density lipoprotein cholesterol levels after discharge for acute myocardial infarction in a real-world patient population.

Aggressively managing low-density lipoprotein cholesterol (LDL-C) after myocardial infarction (MI) is a cornerstone of secondary prevention. The changes in LDL-C after MI and the factors associated with LDL-C levels are unknown. Therefore, we directly measured fasting LDL-C levels in 797 MI patients from 24 US hospitals from 2005 to 2008. Mean LDL-C levels at discharge, 1 month, and 6 months were 95.1, 81.9, and 87.1 mg/dL, respectively. In a hierarchical, multivariable, repeated measures model, older age, male sex, and hypertension were associated with lower LDL-C levels, whereas self-reported avoidance of health care because of cost was associated with higher LDL-C. Both the presence and intensity of statin therapy at discharge were strongly associated with LDL-C levels, with adjusted mean 6-month changes of -3.4 mg/dL (95% confidence interval (CI): -12.1, 5.3) for no statins; 1.7 mg/dL (95% CI: -4.7, 8.1) for low statins; -10.2 mg/dL (95% CI: -14.5, -6.0) for moderate statins; and -13.9 mg/dL (95% CI: -19.7, -8.0) for intensive statins (P < 0.001). In conclusion, we found that greater reductions in LDL-C levels after MI were strongly associated with the presence and intensity of statin therapy, older age, male sex, hypertension, and better socioeconomic status. These findings support the use of intensive statin therapy in post-MI patients and provide estimates of the expected LDL-C changes after MI in a real-world population.

[Pathogenic mechanisms of proatherogenic changes in pregnant women with concomitant obesity].

The concentration of insulin, high sensitivity C-reactive protein (CRP) and indices of lipid metabolism (concentrations of triacylglycerols, total cholesterol, cholesterol of low density lipoproteins and cholesterol of very low density lipoproteins) in women with concomitant obesity in the second trimester of pregnancy were studied. Changes of the lipid profile in the pregnant women with concomitant obesity indicate development of type IV hyperlipoproteinemia. Concentrations of insulin and CRP in the blood serum of the pregnant women with obesity were respectively 92.1% and 62.5% higher than in the control group. On the basis of literature data and our own research it was concluded that the complex of the metabolic changes (insulin resistance, dislipidemia, endothelial dysfunction, systemic inflammation) in pregnant women with obesity promotes development of proatherogenic changes.

Elevated lipoprotein(a) in a newborn with thrombosis and a family history of dyslipidemia.

This paper reports a rare case of elevated lipoproteinemia(a) that evolved into thrombosis during the neonatal period. During the first days of life, the patient presented with an intracardiac thrombus, pulmonary thromboembolism and a hemorrhagic stroke. Initially, the results of the blood tests performed to screen for thrombophilic diseases were normal for the patient's age. The maternal dyslipidemia and the family's positive history of thromboembolism drew attention to an underlying, inherited, thrombophilic defect. Upon further investigation of the thrombophilia, the increase in lipoprotein(a) levels found in the mother and infant enabled the diagnosis of hyperlipoprotein(a) and the administration of appropriate therapy.

Vitamin D, metabolic dyslipidemia, and metabolic syndrome in rheumatoid arthritis.

PURPOSE: Vitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated the associations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoid arthritis, a group at high risk for cardiovascular disease. METHODS: Serum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of 499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORE Trial). Participants had rheumatoid arthritis with active disease, and were naïve to methotrexate and biologic therapies. Multivariable linear regression was performed to assess associations between vitamin D levels and lipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemia and the metabolic syndrome in participants with vitamin D deficiency (<20 ng/mL). RESULTS: In multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inversely with low-density lipoprotein (ß: -0.029 [-0.049, -0.0091], P=.004) and triglyceride (ß: -0.094 [-0.15, -0.039] P=.001) levels, adjusted for demographic, cardiovascular, and disease-specific variables. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariate analyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemia (odds ratio 1.72; 95% confidence interval, 1.10-2.45; P=.014) and metabolic syndrome (odds ratio 3.45; 95% confidence interval, 1.75-6.80; P <.001) in adjusted models. CONCLUSIONS: In conclusion, vitamin D deficiency was associated with the metabolic syndrome and dyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale, prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels and reduces cardiovascular risk in rheumatoid arthritis.

Hypolipidimic and antioxidant activities of virgin olive oil and its fractions in 2,4-diclorophenoxyacetic acid-treated rats.

OBJECTIVE: We examined the effects of extra virgin olive oil (EVOO) and its hydrophilic and lipophilic fractions on serum lipids, oxidative stress, and morphologic and functional liver damages induced by 2,4-diclorophenoxyacetic acid (2,4-D). METHODS: Male Wistar rats were divided randomly into eight groups: control; 2,4-D at a dose of 5 mg/kg of body weight (2,4-D); 2,4-D plus EVOO (2,4-D/EVOO); 2,4-D plus the hydrophilic fraction (2,4-D/OOHF); 2,4-D plus the lipophilic fraction (2,4-D/OOLF); only EVOO (EVOO); only the hydrophilic fraction (OOHF); and only the lipophilic fraction (OOLF). These components were administered daily by gavage for 4 wk. RESULTS: A hepatic architecture aberration, increased activities of aspartate and alanine aminotransferase enzymes, total and low-density lipoprotein cholesterol, and malondialdehyde (MDA) level, and a decreased antioxidant defense system were observed in the 2,4-D group. The administration of EVOO restored the damage caused by 2,4-D by a significant decrease of plasma total and low-density lipoprotein levels and a moderate increase of high-density lipoprotein cholesterol. The 2,4-D/OOHF group exhibited a pronounced enhancement of the antioxidant defense system by an increase of superoxide dismutase, catalase, and glutathione peroxidase levels and a decrease of plasma and liver MDA levels. However, less improvement in the liver histoarchitecture and antioxidant status was observed in rats supplemented with OOLF diet, despite its richness in α-tocopherol. CONCLUSION: Extra virgin olive oil may be a potential functional food source of antioxidants than can decrease the frequency of cardiovascular diseases and liver damage.

[Pleiotropic effects of nicotinic acid therapy in men with coronary heart disease and elevated lipoprotein(a) levels].

PURPOSE: To assess effects of niacin on risk factors of atherosclerosis in men with coronary heart disease (CHD) and high lipoprotein(a) [Lp(a)] levels. MATERIAL AND METHODS: Sixty men (mean age 54+/-6 years) with angiographic evidence of CHD were randomized into two groups. Active group (n=30) received extended release nicotinic acid 1500 mg, control group consisted of remaining 30 patients. All patients received basic therapy with atorvastatin 10-40 mg qd. Blood samples were collected for total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), Lp(a), lipoprotein-associated phospholipase A2 (Lp-PL-2), high-sensitivity C-reactive protein (hsCRP), complex of tissue-type plasminogen activator with plasminogen activator inhibitor type 1 (tPA/PAI-1). Carotid intima media thickness (CIMT) was measured at baseline and after 6-months therapy. RESULTS: There was no statistically significant difference between the groups in the clinical and biochemical characteristics. During the study lipid profile data were within the target levels. In the active group median percent decrease of Lp(a) level was 23% (from 84+/-40 to 67+/-25 mg/dl after 6 weeks and up to 65+/-37 mg/dl after 6 months of treatment, p<0.01); LDL-C, TG, tPA/PAI-1, and Lp-PL-2 mass levels decreased by 25, 20, 25, and 32%, respectively; HDL-C increased by 16% (p<0.05 vs baseline, respectively). Nicotinic acid treatment produced statistically significant reduction nicotinic acid of the mean CIMT (right: 0.83+/-0.16 vs 0.77+/-0.17 mm, p<0.05; left: 0.88+/-0.21 vs 0.82+/-0.17, p<0.05). In control group no changes of CIMT or blood tests were observed. CONCLUSION: In men with CHD and Lp(a) excess of addition to atorvastatin results in regression of CIMT on an average of 0.06 mm in 6 months. Such rapid and significant effect on the arterial wall structure can be attributed to the complex influence of nicotinic acid on Lp(a), lipids, Lp-PL-2 and thrombogenic factors. This is the first study providing the evidence of using Lp(a) as one of therapeutic targets in patients with high Lp(a) levels for achieving beneficial effect on a surrogate marker of atherosclerosis.

[Treating the symptoms in nephrotic syndrome: which therapeutic strategies are evidence based in the treatment of proteinuria?]. / Symptomatische Therapie bei nephrotischem Syndrom: Was ist gesichert in der Therapie der Proteinurie?.

Glomerular diseases are among the most common renal pathologies leading frequently to end-stage renal disease. Clinical disease can be divided into five different groups the features of which are determined by the underlying pathophysiology. One of these five clinical syndromes is the nephrotic syndrome, which is characterized by proteinuria > 3.5 g/day accompanied by hypalbuminemia, hyperlipoproteinemia and pronounced edema. The nephrotic syndrome may be the clinical manifestation of a row of underlying diseases. The pathophysiological basics had remained elusive for decades, yet recently significant progress which allows for establishing new therapeutic strategies has been made. A major breakthrough in understanding the function of the glomerular filter unit has been possible in the last years through both genetic and cell biological studies, which have revealed a crucial role for the visceral epithelial cells of the glomerulus - the podocytes. By now various factors have been found causing podocyte damage, such as toxines, immunological phenomena or systemic disease like diabetes mellitus.

Effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein, lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia.

Inflammation, oxidative stress, and high concentration of serum lipoprotein (a) [Lp (a)] are common complications in hemodialysis patients. The present study was designed to investigate the effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein (CRP), Lp (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia [hyper Lp (a)]. This was an unblinded, randomized clinical trial. Thirty-six hyper Lp (a) hemodialysis patients (23 men and 13 women) were randomly assigned to either a carnitine or control group. Patients in the carnitine group received 1000 mg/d oral L-carnitine for 12 weeks, whereas patients in the control group did not receive any L-carnitine supplement. At baseline and the end of week 12, 5 mL of blood were collected after a 12- to 14-hours fast and serum free carnitine, CRP, interleukin-1ß, interleukin-6 (IL-6), tumor necrosis factor-α, Lp (a), and oxidized low-density lipoprotein were measured. Serum free carnitine concentration increased significantly by 86% in the carnitine group at the end of week 12 compared with baseline (P<0.001), while serum CRP and IL-6 showed a significant decrease of 29% (P<0.05) and 61% (P<0.001), respectively. No significant changes were observed in serum free carnitine, CRP, and IL-6 in the control group. There were no significant differences between the two groups in mean changes of serum interleukin-1ß, tumor necrosis factor-α, Lp (a), and oxidized low-density lipoprotein concentrations. L-carnitine supplement reduces inflammation in hemodialysis patients, but has no effect on hyper Lp (a) and oxidative stress.

Links between enhanced fatty acid flux, protein kinase C and NFkappaB activation, and apoB-lipoprotein production in the fructose-fed hamster model of insulin resistance.

In the current study, we show evidence, in a fructose-fed hamster model of insulin resistance, that free fatty acid (FFA) can induce hepatic insulin resistance in part via PKC activation leading to increased production of atherogenic apoB100-containing lipoproteins. Interestingly, IkappaB-kinase beta (IKKbeta)-dependent NF-kappaB was activated in hepatocytes from the fructose-fed hamster as an indication for PKC activation. Treatment of hepatocytes with oleate for 16h showed the activation of the PKC isoforms, PKCalpha/betaII, in a dose dependent manner. Strikingly, the general PKC inhibitor, bisindolylmaleimide-I, Bis-I (5 microM) was found to ameliorate fructose-induced insulin resistance, restoring the phosphorylation status of PKB and suppressing apoB100 overproduction in ex vivo and in vivo. The data suggest that hepatic PKC activation, induced by increased circulating FFA may be an important factor in the development of insulin resistance and dyslipidemia seen in the fructose-fed hamster model.

[Lipids abnormalities in children with refractory nephrotic proteinuria]. / Zaburzenia lipidowe u dzieci z nawrotami bialkomoczu nerczycowego.

UNLABELLED: The aim of the study is to evaluate the lipids disorders in children with refractory proteinuria in acute phase and remission of the disease. The study group consist of 39 children, mean age 8.2 +/- 3.9 years with refractory nephrotic syndrome (RNS)/nephrotic proteinuria (RNP), wchich were divided in 3 groups according to RNS/RNP frequency: group A--17 children up to 3 times, group B--13 children 4-9 times, group C--9 children > or = 10 times. Total number of relapses was 53. In all children at the start and every 3 months, the total cholesterol concentration (TC), LDL, HDL cholesterol, triglicerydes (TG), apolipoprotein A1(apoA1), apoliporotein B100 (apoB100 ) were measured. The duration of the study was 12 months. RESULTS: Children with NS/NP in the acute phase of the disease show high levels of TC, TG, LDL-C and apolipoproteins: apo AI, apo B100, The level of HDL-C was normal. In the groups A, B, C a normalization of average levels of apo B100, was recorded after 3 month, apo AI after 3 to 6 months. With the increasing amount of relapses the time to normalization of average levels of TC and LDL-C was prolonged. Normal average levels of LDL-C were recorded in the group A after 3 months, in the group B after 9 months, in the group C was still high. TC normalization was recorded after 6 months only in the group A, in the groups B and C the level was high; TG was high during 12 months of observation in all groups. CONCLUSION: The persistance of high TC, LDL-C and TG levels during the remission phase in children with higher numbers of NS/NP relapses is a risk factor of atherosclerosis developement.

Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese.

Plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins. Since CETP regulates the plasma levels of HDL cholesterol and the size of HDL particles, CETP is considered to be a key protein in reverse cholesterol transport (RCT), a protective system against atherosclerosis. The importance of plasma CETP in lipoprotein metabolism was demonstrated by the discovery of CETP-deficient subjects with marked hyperalphalipoproteinemia (HALP). Genetic CETP deficiency is the most important and common cause of HALP in the Japanese. Ten mutations of the CETP gene have been demonstrated as causes of HALP, including two common mutations: an intron 14 splicing defect (Int14 + 1 G --> A) and an exon 15 missense mutation (D442G). The subjects with CETP deficiency show a variety of abnormalities in the concentration, composition, and function of both HDL and low density lipoprotein (LDL). CETP deficiency is considered a physiological state of impaired RCT, which may possibly lead to the development of atherosclerosis despite high HDL cholesterol levels. However, the pathophysiological significance of CETP in terms of atherosclerosis has been controversial. Epidemiological studies in Japanese-Americans living in Hawaii and Japanese in the Omagari area, where HALP subjects with an intron 14 splicing defect of the CETP gene are markedly frequent, have shown a relatively increased incidence of coronary atherosclerosis in CETP deficiency. On the other hand, the TaqIB polymorphism-B2 allele with low CETP mass and increased HDL cholesterol has been related to a decreased risk for coronary heart disease (CHD) in many studies, including the Framingham Offspring Study. The current review focused on the characterization of the Japanese subjects with CETP deficiency, including our recent findings.