Glycaemic Influences on the ATP-Binding Cassette Transporter A1 (ABCA1)

Increased glucose levels are associated with increased risk of vascular disease. The risk is elevated 2-4 fold in type 2 diabetes and there is a positive relationship between glucose (or HbA1c) levels and vascular disease in the general population. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT) by studying an early key step, notably the expression and activity of the ATP binding cassette transporter-A1 (ABCA1). This protein exports cellular cholesterol to apolipoprotein A1 (ApoA-I), thereby forming nascent HDL. In this thesis, it is shown that ABCA1 gene expression in leukocytes in men is reduced in Type 2 diabetes and correlates negatively with circulating HbA1c levels and fasting glucose. This confirms our earlier findings in healthy men. An independent relationship between glycaemia and leukocyte ABCG1 gene expression was not seen. ABCA1 protein concentrations in blood leukocytes were reduced in patients with diabetes. ApoA-I-mediated cholesterol efflux in cultured fibroblasts taken from subjects was studied as a measure of ABCA1 function. This negatively associated with fasting glucose at the time of sampling as well as adiposity. Cellular cholesterol removal was reduced in subjects with diabetes compared with controls. There was a positive relationship between both ABCA1 function and leukocyte protein concentration with circulating HDL cholesterol. These relationships were independent of expression of liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). These data imply a persistent glycaemia-mediated suppression of an early step in RCT which may contribute to the excess vascular disease observed in such patients. It further proposes impaired cholesterol efflux may contribute to the low circulating HDL cholesterol which is commonly seen in patients with impaired glucose regulation