Type 2 Diabetes Is Associated with Reduced ATP-Binding Cassette Transporter A1 Gene Expression, Protein and Function

Abstract

ObjectiveIncreasing 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 ResultsLeukocyte 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.

Investigation of ABCA1 C69T polymorphism in patients with type 2 diabetes mellitus

“…In another study, Patel et al . indicated that ABCA1 expression and protein concentrations in leukocytes, as well as function in cultured skin fibroblasts, are reduced in type 2 diabetic patients (20). Brunham et al .…”

The Effects of Rope Training on Lymphocyte ABCA1 Expression, Plasma ApoA-I and HDL-c in Boy Adolescents

“…ELISA assay of this protein on cell lysis had been previously reported (24). Frist, after preparing cell lysates by lysis buffer (Tris 50 mM , 5 Mm EDTA , 1% Triton X-100, pH 7.6) containing complete protease inhibitor (pro-block cocktails anti-protease, manufacturers Gouldbio Inc. USA) which were performed on ice, supernatants containing clear cell lysates were collected after centrifugation at 15,000 rpm for 15 minutes at 4 ° C by refrigerated centrifuge (Hythe, Germany).…”

Myeloid cell-specific ABCA1 deletion does not worsen insulin resistance in HF diet-induced or genetically obese mouse models

“…We previously demonstrated that myeloid cell-specifi c deletion of ABCA1 results in increased macrophage infl ammatory response to TLR agonists ( 24 ), and human studies suggest an association between ABCA1 single nucleotide polymorphisms, leukocyte ABCA1 expression, and insulin resistance (17)(18)(19)(20)(21)(22). However, whether there is a link between macrophage ABCA1-regulated innate immunity and insulin resistance is unknown.…”

“…However, ABCA1 single nucleotide polymorphisms are associated with altered glucose metabolism and insulin resistance in humans (17)(18)(19)(20). Of interest, leukocyte ABCA1 gene expression is associated with fasting glucose concentrations in normoglycemic men, and reduced leukocyte ABCA1 gene expression is associated with type 2 diabetes ( 21,22 ). To date, only one study has directly linked ABCA1 expression to hyperglycemia, reporting that pancreatic ␤ cell-specifi c ABCA1 deletion results in defective insulin release from islet cells ( 23 ).…”