Association between serum retinol-binding protein 4 and small dense low-density lipoprotein cholesterol levels in young adult women

BackgroundSerum retinol-binding protein 4 (RBP4) and small dense low-density lipoprotein (sdLDL) have been suggested to be associated with insulin resistance, but no information is available on the relationship between RBP4 and sdLDL.MethodsWe determined serum RBP4, sdLDL-cholesterol, and other metabolic variables on 38 young women, aged 19–29 years. The homeostatic model assessment of insulin resistance (HOMA-IR) was used for the estimation of insulin resistance.ResultsIn simple regression analyses, RBP4 levels had significant correlations with total cholesterol (r = 0.354, P = 0.029), LDL-cholesterol (r = 0.396, P = 0.014), and sdLDL-cholesterol (r = 0.510, P = 0.001) levels. The sdLDL-cholesterol levels also correlated significantly with total cholesterol (r = 0.402, P = 0.012), LDL-cholesterol (r = 0.627, P < 0.001) and triglycerides (r = 0.449, P = 0.005). Stepwise multiple regression analyses showed only sdLDL-cholesterol (β coefficient (ß) = 0.510, P = 0.001) level was a significant independent predictor of RBP4 levels (adjusted R² = 0.240), whereas RBP4 (ß = 0.289, P = 0.026) level was one of major factors affecting sdLDL-cholesterol levels (adjusted R² = 0.519). There was no significant association of HOMA-IR with RBP4 or sdLDL levels.ConclusionsWe showed an independent linkage between serum RBP4 and sdLDL-cholesterol levels in young adult women. These findings may contribute to understanding of lipoprotein metabolisms involved in diabetes and cardiovascular disease.     

CETP and oxidized LDL levels increase in dyslipidemic subjects

OBJECTIVES: To explore the possible associations among cholesteryl ester transfer protein (CETP), contents of lipids in low-density lipoprotein (LDL), and in vivo oxidized LDL (Ox-LDL). DESIGN AND METHODS: CETP and Ox-LDL were both detected by ELISA. Their levels and the lipid contents of LDL were investigated in 200 subjects with various dyslipidaemias. RESULTS: Compared to the control, CETP levels were significantly increased in subjects with mixed hyperlipidaemia and hypercholesterolaemic. Ox-LDL levels were only significantly increased in mixed hyperlipidaemia subjects. Triacyglycerols to cholesterol ratio in LDL was significantly increased in various dyslipidaemias subjects, of which, hypertriglyceridaemic subjects exhibited the most significant change, while hypercholesterolaemic subjects the least. Multiple linear regression analysis showed that total cholesterol and triacyglycerols levels in very low-density lipoprotein were significantly related with CETP (R(2)=0.066), and triacyglycerols and total cholesterol levels were significantly related with Ox-LDL (R(2)=0.094), respectively. CONCLUSIONS: High CETP promotes the transport of lipids among lipoproteins, which changed the lipid composition of LDL, resulting in the increase of in vivo Ox-LDL level, and subsequently contributing to the atherogenic process in dyslipidaemias subjects.     

Decreased small dense LDL levels in Gilbert's syndrome

Objective

To investigate the role of small dense low density lipoprotein cholesterol (sd-LDL-C) in the mechanism of decreased incidence of cardiovascular disease in Gilbert's syndrome (GS).

Design and methods

sd-LDL-C, ox-LDL, and high sensitive C reactive protein (hs-CRP) levels were investigated in subjects with GS (n = 42) and compared to healthy controls (n = 52).

Results

Age, gender and body mass index (BMI) distributions were similar between the two groups. sd-LDL-C, ox-LDL and hs-CRP levels were lower in GS than the healthy controls (p < 0.001, p < 0.001 and p = 0.001, respectively). Unconjugated bilirubin was negatively correlated with sd-LDL-C, ox-LDL and hs-CRP (r = −0.594, p < 0.001; r = −0.249, p = 0.016 and r = − 0.373, p < 0.001 respectively). In addition, sd-LDL-C was positively correlated with ox-LDL (r = 0.307, p = 0.003).

Conclusions

The findings of this preliminary study suggest that reduced sd-LDL-C, ox-LDL and hs-CRP levels may have a role in preventing atherosclerosis in subjects with GS.     

小而密低密度脂蛋白胆固醇与 ２ 型糖尿病微血管病变 的相关性分析

摘要：目的 探讨小而密低密度脂蛋白胆固醇（ｓｄＬＤＬ Ｃ）与 ２ 型糖尿病微血管病变之间的关系。方法 （１）检索 ＰｕｂＭｅｄ、Ｔｈｅ Ｃｏｃｈｒａｎｅ Ｌｉｂｒａｒｙ、ＥＭｂａｓｅ、ＣＮＫＩ、ＶＩＰ、万方数据库及 ＣＢＭ 等数据库，收集 ｓｄＬＤＬ Ｃ 与 ２ 型糖尿病微血管病变相关的文献，检索 时限为建库至 ２０２１ 年７ 月，提取相关数据，并用ｓｔａｔａ１６．０ 软件进行分析。（２）收集武汉大学中南医院２０１９ 年３ 月至２０２１ 年２ 月确诊的 ３０５ 例 ２ 型糖尿病（Ｔ２ＤＭ）患者，其中单纯 Ｔ２ＤＭ 患者（对照组）１１９ 例，Ｔ２ＤＭ 微血管病变患者（病例组）１８６ 例。测 定所有患者的血清 ｓｄＬＤＬ Ｃ 及其他相关临床代谢指标，采用 ＳＰＳＳ２６．０ 软件对收集的数据进行处理与分析。结果 （１）本次 Ｍｅｔａ 分析共纳入 ６ 篇病例对照研究，１ ５９７ 例患者符合纳入标准，单纯 Ｔ２ＤＭ 患者（对照组）６４２ 例，Ｔ２ＤＭ 微血管病变患者（病 例组）９５５ 例。Ｍｅｔａ 分析结果显示，与对照组比较，病例组患者的血清 ｓｄＬＤＬ Ｃ 水平明显升高，差异具有统计学意义（ＳＭＤ ＝ ０．５６，９５％ＣＩ：０．３３～ ０．７８，Ｐ＜０．００１）。Ｂｅｇｇ′ｓ 检验和 Ｅｇｇｅｒ′ｓ 检验结果显示各项研究间无明显的发表偏倚，敏感度分析认为本次 Ｍｅｔａ 分析结果具有稳定性与可靠性。（２）回顾性分析 ３０５ 例 Ｔ２ＤＭ 患者，对照组和病例组患者的 ｓｄＬＤＬ Ｃ、ＴＣ、ＴＧ、Ｌｐ（ａ）、 ＦＰＧ、Ｃｒ 及 Ｔ Ｂｉｌ 存在差异，其中病例组患者的 ｓｄＬＤＬ Ｃ 水平显著高于对照组（Ｐ＜０．００１）；而性别、年龄、ＨＤＬ Ｃ 及 ＬＤＬ Ｃ 差异 无统计学意义（Ｐ＞０．０５）。多因素 Ｌｏｇｉｓｔｉｃ 回归分析结果显示 ｓｄＬＤＬ Ｃ 是 Ｔ２ＤＭ 患者并发微血管病变的独立危险因素（Ｐ＜ ０．０１）。结论 糖尿病微血管病变患者 ｓｄＬＤＬ Ｃ 水平明显高于单纯 Ｔ２ＤＭ 患者，ｓｄＬＤＬ Ｃ 可能是糖尿病微血管病变的危险因素。     

Plasma phospholipid transfer protein activity and small,dense LDL in type 2 diabetes mellitus

BACKGROUND: Phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) remodel circulating lipoproteins and play a role in the antiatherogenic reverse cholesterol transport pathway. The present study determined whether abnormalities in the LDL subfraction pattern in type 2 diabetic patients were related to changes in lipid transfer proteins. METHODS: Low-density lipoprotein (LDL) subfractions were measured by density gradient ultracentrifugation and plasma PLTP and CETP activities by radiometric assays in 240 diabetic patients and 136 controls. RESULTS: The diabetic patients had lower LDL-I (P < 0.001) and higher LDL-III concentrations than the controls (P < 0.001). Plasma PLTP activity was increased (P < 0.001) whereas no significant differences were seen in CETP activity. In the diabetic patients, small, dense LDL-III correlated with plasma triglyceride (r = 0.18, P < 0.01), HDL (r = -0.14, P < 0.05), PLTP (r = 0.29, P < 0.001) and CETP activity (r = 0.15, P < 0.05). Linear regression analysis showed that plasma PLTP activity, triglyceride and age were the major determinants of LDL-III concentration (r2 = 28%, P < 0.001). The univariate relationship between CETP and LDL-III was no longer significant after adjusting for PLTP activity. CONCLUSIONS: The increase in plasma PLTP activity was independently associated with small, dense LDL concentrations in type 2 diabetes. Hence, elevated PLTP activity might have both antiatherogenic and pro-atherogenic potential in these patients.     

Association between measured or calculated small dense low‐density lipoprotein cholesterol and oxidized low‐density lipoprotein in subjects with or without type 2 diabetes mellitus

BackgroundSmall dense low‐density lipoprotein (sdLDL) possesses atherogenic potential and is predicted to be susceptible to atherogenic modifications, which further increases its atherogenicity. However, studies on the association between measured or estimated sdLDL cholesterol (sdLDL‐C) levels and atherogenic modification in diverse population groups are lacking.MethodsSurplus serum samples were collected from male subjects with type 2 diabetes mellitus (DM) under treatment (n = 300) and without DM (non‐DM; n = 150). sdLDL and oxidized LDL (oxLDL) levels were measured using the Lipoprint LDL subfractions kit (Quantimetrix Corporation) and the Mercodia oxidized LDL competitive enzyme‐linked immunosorbent assay kit (Mercodia), respectively. The estimated sdLDL‐Cs were calculated from two relevant equations. The effects of sdLDL‐C on oxLDL were assessed using multiple linear regression (MLR) models.ResultsThe mean (±SD) of measured sdLDL‐C and oxLDL concentrations were 11.8 ± 10.0 mg/dl and 53.4 ± 14.2 U/L in the non‐DM group and 0.20 ± 0.81 mg/dl and 46.0 ± 15.3 U/L in the DM group, respectively. The effects of measured sdLDL‐Cs were significant (p = 0.031), whereas those of estimated sdLDL‐Cs were not (p = 0.060, p = 0.116) in the non‐DM group in the MLR models. The effects of sdLDL‐Cs in the DM group were not significant.ConclusionIn the general population, high level of sdLDL‐C appeared to be associated with high level of oxLDL. The equation for estimating sdLDL‐C developed from a general population should be applied with caution to a special population, such as patients with DM on treatment.     

2型糖尿病患者血清小而密低密度脂蛋白胆固醇水平与脂类代谢异常及胰岛素抵抗的关系

目的探讨2型糖尿病患者血清小而密低密度脂蛋白胆固醇（sdLDL-C）水平与脂类代谢异常及胰岛素抵抗的关系。方法 193例2型糖尿病患者按胰岛素抵抗情况分为胰岛素抵抗组144例与非胰岛素抵抗组49例。采用奥林巴斯AU2700全自动生化仪检测血清小而密低密度脂蛋白（sdLDL-C）、三酰甘油（TG）、总胆固醇（TC）、空腹血糖（FBG）等,采用化学发光法检测空腹胰岛素（FIN）、C肽,并计算胰岛素抵抗指数（HOMA-IR）等。结果 2型糖尿病患者中,与非胰岛素抵抗组相比,胰岛素抵抗组TG、TG/高密度脂蛋白（HDL）、TC/HDL、sdLDL-C水平显著升高（P〈0.05）,而HDL、载脂蛋白A（apo AⅠ）、脂蛋白（Lpa）水平显著降低（P〈0.05）;对2型糖尿病患者sdLDL-C、胰岛素抵抗指数进行多元逐步回归分析,sdLDL-C与TG（Log）、LDL-C/HDLC及TG/HDL-C（Log）呈正相比关性（r=0.638、0.601、0.290,P〈0.01）,与TG/HDL（Log）和LDL-C/apoB呈负相关关系（r=-0.589、-0.342,P〈0.01）;HOMA-IR与TG/HDL和sdLDL-C呈正相关关系（r=0.281、0.250,P〈0.01）,而与TC呈负相关（r=-0.233,P〈0.01）。结论 SdLDL-C能较好地反映2型糖尿病患者胰岛素抵抗对脂类代谢的影响,TG/HDL-C、LDL-C/HDL-C等提供的重要临床信息应在以后的临床应用中得到进一步认识和重视。     

Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects.

A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (>1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (<1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (<1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P<0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r=-0.57; P<0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.     

Impact of antiretroviral therapy on visfatin and retinol-binding protein 4 in HIV-infected subjects

Background To determine circulating levels of adipocytokines, especially the recently characterized visfatin, and the fat‐derived factor retinol‐binding protein‐4 (RBP‐4) in HIV‐infected subjects and their respective changes following treatment with highly active antiretroviral therapy (HAART). Materials and methods Fourteen HIV‐positive, HAART‐naïve subjects were compared with 10 HIV‐negative healthy controls and reassessed after a 1‐year treatment with HAART. Plasma visfatin and RBP‐4 were determined by ELISA, whereas leptin and adiponectin by RIA. Body composition was measured with dual X‐ray absorptiometry (DXA). Homeostasis model assessment (HOMA‐IR) was assessed using insulin and glucose levels. Results Visfatin and RBP‐4 levels in HIV‐positive subjects were comparable with those of HIV‐negative controls before treatment with HAART. Treatment with HAART for 12 months resulted in a 6·9‐fold and 7·1‐fold increase of visfatin and RBP‐4 levels (+54·0 ± 9·7 ng mL^?1, P < 0·0001 and +95·3 ± 31·7 ng mL^?1, P < 0·01), respectively. Leptin (?2·7 ± 1·6 ng mL^?1, P = 0·054) was unchanged and adiponectin (?2·8 ± 0·7 µg mL^?1, P < 0·01) decreased. Changes of visfatin concentrations correlated significantly with the increases of RBP‐4 (r = 0·78, P = 0·001), fat‐free mass (FFM, r = 0·75, P < 0·05) and change of HOMA‐IR (r = 0·64, P < 0·05). Parameters of glucose metabolism and body fat mass were unchanged during the observation period. Conclusions Treatment with HAART induced a pronounced increase of plasma visfatin and RBP‐4 as well as a decrease of adiponectin in HIV‐infected patients on HAART. Although body weight, fat mass and parameters of glucose metabolism remained stable, the changes in the adipocytokines might herald subsequent alterations of these parameters.     

Evaluation of a new homogenous method for detection of small dense LDL cholesterol: Comparison with the LDL cholesterol profile obtained by density gradient ultracentrifugation

BackgroundSmall, dense LDL (sdLDL) are highly atherogenic, and evidence indicates that sdLDL are useful predictors of cardiovascular disease. We evaluated a homogeneous method for the quantitative determination of sdLDL cholesterol (sdLDL-C) and compared it to the LDL-cholesterol profile obtained by density gradient ultracentrifugation (DGUC).MethodssdLDL-C was measured in plasma and in lipoprotein fractions obtained by DGUC using the sdLDL-EX “Seiken” kit.ResultssdLDL-C was only present in dense or intermediate LDL fractions obtained by DGUC. Plasma sdLDL-C levels were inversely corelated to the LDL relative floatation rate. The proportion of LDL-C that is sdLDL-C increases as a function of LDL density from a median of 19% for very buoyant LDL to 91% for very dense LDL particles. Plasma sdLDL-C level was significantly correlated with plasma triglyceride (TG) (n = 840, r_s = 0.710, p < 0.001). Among subjects with plasma TG > 150 mg/dl, 75% had sdLDL-C > 30 mg/dl, whereas among those with TG ≤ 150 mg/dl, only 17% had sdLDL-C > 30 mg/dl.ConclusionsThis precise and fully automated method for measuring plasma levels of sdLDL-C will allow the analysis of large number of samples in routine laboratories which will facilitate the evaluation of the clinical usefulness of sdLDL as a risk factor for CHD.     

Circulating small dense LDL, endothelial injuring factors and fibronectin in healthy postmenopausal women

BACKGROUND: In postmenopausal women (PMW), an adverse lipoprotein pattern and high risk of coronary artery disease has been described. Studies of the mechanisms promoting the higher atherogenic risk observed in healthy PMW are relevant. We evaluated the interactions among several circulating factors involved in the endothelial injury and inflammation in relation to LDL characteristics, beyond LDL cholesterol. METHODS: Lipoprotein profile, including apolipoproteins A-I and B, small dense LDL, hepatic lipase, cholesterol transfer protein (CETP), LDL composition and oxidability were assessed in PMW (n=30) in comparison to premenopausal (PreMW, n=28). The following emerging factors were measured: homocysteine, phospholipase A2, ferritin, hs-CRP and fibronectin from extracellular vascular matrix. Insulin-resistance was evaluated by waist circumference, HOMA and TG/HDL cholesterol ratios. RESULTS: The risk index apo B/apo A-I was significantly increased in PMW (p<0.0001), PMW showed higher proportion of small dense LDL which correlated with the increase in hepatic lipase activity (p<0.005) and with insulin-resistance markers (p<0.05), but not with CETP. Phospholipase A2 (p<0.05), homocysteine (p<0.005), hs-CRP (p<0.005), fibronectin (p<0.05) and ferritin (p<0.0001) were increased in PMW. LDL oxidability positively correlated with waist (p<0.02), homocysteine (p<0.05), fibronectin (p<0.05), hs-CRP (p<0.04), phospholipase A2 (p<0.05), and small dense LDL (p<0.01). After adjusting by menopausal condition, age and waist, LDL oxidability remained associated with waist (beta: 0.35, p=0.047), homocysteine (beta: 0,36 p<0,038), fibronectin (beta: 0,41 p=0.05), and small dense LDL (beta: 0.36, p=0.027). CONCLUSIONS: Evaluation of classic and non-traditional circulating risk factors in hypoestrogenism reflected endothelial and subendothelial inflammation and subclinical atherogenic processes.     

Effects of LDL, cholesterol, and their oxidized forms on the precipitation kinetics of calcium phosphates

BACKGROUND: LDL, cholesterol, and their oxidized forms are known cardiovascular risk factors and are often found in atherosclerotic lesions of various stages. Little is known, however, about whether they are directly involved in the formation of calcium phosphate compounds. METHODS: We used the pH-stat technique to follow the kinetics of calcium phosphate precipitation at pH 7.4, 37 degrees C, and ionic strength 0.150 mol/L, in the presence or absence of LDL, oxidized LDL, cholesterol, cholestane-3beta,5alpha,6beta-triol, and cholesteryl linoleate. The precipitates were characterized by x-ray diffraction, scanning and transmission electronic microscopy coupled with energy-dispersion x-ray analysis, and inductively coupled plasma atomic emission spectroscopy. RESULTS: Under the experimental conditions, LDL (14.8 and 43.1 mg/L protein) had no significant effect on the precipitation kinetics. Oxidized LDL (14.8 and 43.1 mg/L protein) prolonged the nucleation phase and diminished the amount of total precipitate, and both the extent of oxidation and the concentration of the protein affected the kinetics. Cholesterol microcrystals (71.4 and 143 mg/L) made the nucleation phase shorter (300 min vs 390 min for the control), and the precipitated particles had an organic core and a shell composed of calcium phosphates. L-alpha-Phosphatidylcholine vesicles (143 mg/L), cholesterol (71.4 mg/L)/phospholipid (143 mg/L) mixed vesicles, cholesteryl linoleate (143 mg/L), and cholestane-3beta,5alpha,6beta-triol (71.4 mg/L) prolonged the nucleation phase. CONCLUSIONS: LDL is not involved directly in the precipitation of calcium phosphates. Oxidized LDL inhibits both nucleation and crystal growth, possibly by attracting calcium ions in the solution and thus reducing supersaturation. Cholesterol microcrystals serve as seeds for the precipitation of hydroxyapatite, whereas L-alpha-phosphatidylcholine, cholesteryl linoleate, and cholestane-3beta,5alpha,6beta-triol exhibit inhibitive effects on the nucleation of calcium phosphates.     

Serum total, HDL, LDL cholesterol, and triglyceride levels in patients with rheumatoid arthritis

Patients with rheumatoid arthritis are at risk of increased prevalence of coronary heart disease. In general, the plasma level of high density lipoprotein cholesterol (HDL) correlates with the risk of incidence of ischemic heart disease. The levels of total, HDL, low density (LDL) cholesterol, and triglycerides were measured in sera of patients with rheumatoid arthritis and in healthy controls. In patients with rheumatoid arthritis (26 men and 103 women), the serum total and LDL cholesterol were higher, whereas the HDL cholesterol and triglycerides were lower (p less than 0.001) compared to the values observed in controls (625 men and 749 women). Similar patterns were seen when results of age and sex matched controls were compared to the results of patients suffering from rheumatoid arthritis. The lipid parameters of patients with rheumatoid arthritis were not different when the patients were treated with steroidal or nonsteroidal anti-inflammatory drugs.     

小而密低密度脂蛋白胆固醇与冠状动脉粥样硬化特征的相关性分析

目的结合影像学评价小而密低密度脂蛋白胆固醇(sdLDL-C)与冠状动脉(以下简称"冠脉")粥样硬化病变严重程度的关系。方法连续选取2015年7月至2016年3月阜外医院436例门诊初诊怀疑冠脉粥样硬化性心脏病(CAD)并行冠脉计算机断层摄影术检查(CT)的患者,从斑块性质、病变支数及狭窄程度3个方面分析sdLDL-C与冠脉粥样硬化严重程度的相关性。结果 sdLDL-C与载脂蛋白B(apoB)、三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、血糖(Glu)呈正相关(r依次为0.644、0.631、0.558、0.434、0.145,P均0.01),与高密度脂蛋白胆固醇(HDL-C)呈负相关(r=-0.241,P0.01);sdLDL-C、apoB可作为严重CAD(三支病变及重度狭窄75%)发生的危险因素,且独立于传统风险因素(年龄、性别、高血压史、糖尿病史、吸烟史、饮酒史)及他汀类降脂药的应用;对于三支病变,LDL-C、sdLDL-C、apoB预测价值依次增强(OR依次为1.936、2.673、31.707);对于重度狭窄,LDL-C非独立危险因素,sdLDL-C、apoB有预测价值(OR分别为2.000、9.457)。结论 sdLDL-C可作为独立于传统风险因素的严重CAD预测指标,预测价值优于LDL-C,有可能作为进一步的风险控制指标。