title: Type 2 diabetes is associated with reduced ATP-binding cassette transporter A1 gene expression, protein and function.
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).
  
  
  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.
authors.affiliation: Division of Medicine, Imperial College London, London, United Kingdom. dpatel@doctors.org.uk
authors.forename: Dipesh C
authors.initials: DC
authors.lastname: Patel
authors.forename: Christiane
authors.initials: C
authors.lastname: Albrecht
authors.forename: Darrell
authors.initials: D
authors.lastname: Pavitt
authors.forename: Vijay
authors.initials: V
authors.lastname: Paul
authors.forename: Celine
authors.initials: C
authors.lastname: Pourreyron
authors.forename: Simon P
authors.initials: SP
authors.lastname: Newman
authors.forename: Ian F
authors.initials: IF
authors.lastname: Godsland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Valabhji
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Johnston
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D038321:Glycemic Index; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D012333:RNA, Messenger