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Comparative Study
. 2011;6(7):e22142.
doi: 10.1371/journal.pone.0022142. Epub 2011 Jul 27.

Type 2 diabetes is associated with reduced ATP-binding cassette transporter A1 gene expression, protein and function

Dipesh C Patel  1 , Christiane Albrecht, Darrell Pavitt, Vijay Paul, Celine Pourreyron, Simon P Newman, Ian F Godsland, Jonathan Valabhji, Desmond G Johnston
Affiliations
Comparative Study

Type 2 diabetes is associated with reduced ATP-binding cassette transporter A1 gene expression, protein and function

Dipesh C Patel et al. PLoS One. 2011.

Abstract

Objective: 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).

Methods and results: 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.

Conclusions: 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. ABCA1 gene expression and protein concentration in blood leukocytes is reduced in type 2 diabetes.
A. Leukocyte ABCA1 gene expression, normalised to housekeeper gene (mean and standard error) according to subject glycaemic status in 63 participants. Con = Controls (n = 27), IGH = Impaired glucose regulation (n = 18), DM = type 2 diabetes (n = 18). Con vs. DM; p = 0.03, Con vs. IGH; p = 0.27, IGH vs. DM p = 0.33 (* p<0.05). B. Leukocyte ABCA1 protein concentration (ng/µg protein) expressed as mean and standard error is illustrated according to subject glycaemic status in 50 participants. Con = Controls (n = 17), IGH  = Impaired glucose regulation (n = 17), DM = type 2 diabetes (n = 16) Con vs DM; p = 0.03, Con vs IGH; p = 1; IGH vs DM p = 0.06 (* p<0.05).
Figure 2
Figure 2. Leukocyte ABCA1 gene expression is reduced with increasing glycaemia.
A. Relationship of leukocyte ABCA1 expression (normalised to housekeeper gene) to glycated haemoglobin (HbA1c) in 63 participants (27 control, 18 impaired glucose homeostasis and 18 type 2 diabetes) rho = −0.41, p<0.001. B. Relationship of leukocyte ABCA1 expression (normalised to housekeeper gene) to fasting plasma glucose in 63 participants (27 control, 18 impaired glucose homeostasis and 18 type 2 diabetes) rho = −0.34, p = 0.006.
Figure 3
Figure 3. Cholesterol efflux in skin fibroblasts is reduced in type 2 diabetes and with increasing blood glucose concentration.
A. Cholesterol efflux to Apo-A1 according to glycaemic status in a subgroup of 25 men (Mean and Standard error). 0.5 µCi/ml 1,2-3[H]-cholesterol was loaded onto cells for 24 hours in the presence of 30 µg/ml unlabelled cholesterol. After equilibration, apo-A1 (10 µg/ml) was added to initiate efflux and incubated for 20 hours. Control wells were incubated with culture media alone and apo-A1 mediated efflux was calculated by subtracting background efflux from efflux mediated by apo-A1. Con = Control (n = 9) IGH = Impaired glucose regulation (n = 6), DM = type 2 diabetes (n = 10). Con versus DM; p = 0.04, Con vs. IGH; p = 0.39 (* p<0.05). B. Relationship between fasting glucose and fibroblast apo-AI-mediated cholesterol efflux. rho = −0.50, p = 0.01.
Figure 4
Figure 4. Positive relationship of human ABCA1 measurements with plasma HDL-C concentration.
A. ABCA1 protein concentration in leukocytes positively associates with plasma HDL-C concentration. n = 50, rho = 0.34, p = 0.02. B. Cholesterol efflux to apo-A1 positively relates with plasma HDL-C concentrations. Relationship between ABCA1-mediated cholesterol efflux in fibroblasts (mean of triplicate experiments) and plasma HDL-C concentration. n = 25, rho = 0.41, p = 0.02.
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