Division of Medicine, Imperial College London, London, United Kingdom.
PLoS One. 2011;6(7):e22142. doi: 10.1371/journal.pone.0022142. Epub 2011 Jul 27.
Increasing plasma glucose levels are associated with increasing risk of vascular disease. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT). We studied the influence of plasma glucose on expression and function of a key mediator in RCT, the ATP binding cassette transporter-A1 (ABCA1) and expression of its regulators, liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ).
Leukocyte ABCA1, LXRα and PPARγ expression was measured by polymerase chain reaction in 63 men with varying degrees of glucose homeostasis. ABCA1 protein concentrations were measured in leukocytes. In a sub-group of 25 men, ABCA1 function was quantified as apolipoprotein-A1-mediated cholesterol efflux from 2-3 week cultured skin fibroblasts. Leukocyte ABCA1 expression correlated negatively with circulating HbA1c and glucose (rho = -0.41, p<0.001; rho = -0.34, p = 0.006 respectively) and was reduced in Type 2 diabetes (T2DM) (p = 0.03). Leukocyte ABCA1 protein was lower in T2DM (p = 0.03) and positively associated with plasma HDL cholesterol (HDL-C) (rho = 0.34, p = 0.02). Apolipoprotein-A1-mediated cholesterol efflux correlated negatively with fasting glucose (rho = -0.50, p = 0.01) and positively with HDL-C (rho = 0.41, p = 0.02). It was reduced in T2DM compared with controls (p = 0.04). These relationships were independent of LXRα and PPARγ expression.
ABCA1 expression and protein concentrations in leukocytes, as well as function in cultured skin fibroblasts, are reduced in T2DM. ABCA1 protein concentration and function are associated with HDL-C levels. These findings indicate a glycaemia-related, persistent disruption of a key component of RCT.
升高的血浆葡萄糖水平与血管疾病风险增加相关。我们检验了这样一个假说，即高血糖会损害胆固醇逆转运（RCT）。我们研究了血浆葡萄糖对 RCT 的关键介质——三磷酸腺苷结合盒转运体 A1（ABCA1）的表达和功能，以及其调控因子肝 X 受体-α（LXRα）和过氧化物酶体增殖物激活受体-γ（PPARγ）的表达的影响。
通过聚合酶链反应检测了 63 名血糖状态不同的男性白细胞中的 ABCA1、LXRα 和 PPARγ 表达。通过白细胞测量 ABCA1 蛋白浓度。在 25 名男性的亚组中，通过载脂蛋白 A1 介导的 2-3 周培养的皮肤成纤维细胞胆固醇外流来定量 ABCA1 功能。白细胞 ABCA1 表达与循环 HbA1c 和葡萄糖呈负相关（rho= -0.41，p<0.001；rho= -0.34，p=0.006），且在 2 型糖尿病（T2DM）中降低（p=0.03）。T2DM 患者的白细胞 ABCA1 蛋白水平较低（p=0.03），且与血浆高密度脂蛋白胆固醇（HDL-C）呈正相关（rho=0.34，p=0.02）。载脂蛋白 A1 介导的胆固醇外流与空腹血糖呈负相关（rho= -0.50，p=0.01），与 HDL-C 呈正相关（rho=0.41，p=0.02）。与对照组相比，T2DM 患者的胆固醇外流减少（p=0.04）。这些关系独立于 LXRα 和 PPARγ 的表达。
白细胞中 ABCA1 的表达和蛋白浓度，以及培养的皮肤成纤维细胞中的功能，在 T2DM 中降低。ABCA1 蛋白浓度和功能与 HDL-C 水平相关。这些发现表明，高血糖会导致 RCT 的关键成分持续受到破坏。
