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).

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.

• Authors: Dipesh C Patel, Christiane Albrecht, Darrell Pavitt, Vijay Paul, Celine Pourreyron, Simon P Newman, Ian F Godsland, Jonathan Valabhji, Desmond G Johnston
• Journal: PloS one (PLoS One) Vol. 6 Issue 7 Pg. e22142 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21829447 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters
• Cholesterol, HDL
• Liver X Receptors
• NR1H3 protein, human
• Orphan Nuclear Receptors
• PPAR gamma
• RNA, Messenger

Topics

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Case-Control Studies
• Cells, Cultured
• Cholesterol, HDL (metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Fibroblasts (cytology, metabolism)
• Glycemic Index
• Humans
• Hyperglycemia (genetics, metabolism)
• Liver X Receptors
• Male
• Middle Aged
• Orphan Nuclear Receptors (genetics, metabolism)
• PPAR gamma (genetics, metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin (cytology, metabolism)