RT Journal Article
SR Electronic
T1 Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 2922
OP 2928
DO 10.2337/diabetes.51.10.2922
VO 51
IS 10
A1 Uehara, Yoshinari
A1 Engel, Thomas
A1 Li, Zhengchen
A1 Goepfert, Christian
A1 Rust, Stephan
A1 Zhou, Xiaoqin
A1 Langer, Claus
A1 Schachtrup, Christian
A1 Wiekowski, Johannes
A1 Lorkowski, Stefan
A1 Assmann, Gerd
A1 von Eckardstein, Arnold
YR 2002
UL http://diabetes.diabetesjournals.org/content/51/10/2922.abstract
AB Low HDL cholesterol is a frequent cardiovascular risk factor in diabetes. Because of its pivotal role for the regulation of HDL plasma levels, we investigated in vivo and in vitro regulation of the ATP-binding cassette transporter A1 (ABCA1) by insulin and metabolites accumulating in diabetes. Compared with euglycemic control mice, ABCA1 gene expression was severely decreased in the liver and peritoneal macrophages of diabetic mice. Treatment with insulin restored this deficit. Incubation of cultivated HepG2 hepatocytes and RAW264.7 macrophages with unsaturated fatty acids or acetoacetate, but not with insulin, glucose, saturated fatty acids, or hydroxybutyrate, downregulated ABCA1 mRNA and protein. The suppressive effect of unsaturated fatty acids and acetoacetate became most obvious in cells stimulated with oxysterols or retinoic acid but was independent of the expression of the thereby regulated transcription factors liver-X-receptor α (LXRα) and retinoid-X-receptor α (RXRα), respectively. Unsaturated fatty acids and acetoacetate also reduced ABCA1 promotor activity in RAW264.7 macrophages that were transfected with a 968-bp ABCA1 promotor/luciferase gene construct. As the functional consequence, unsaturated fatty acids and acetoacetate inhibited cholesterol efflux from macrophages. Downregulation of ABCA1 by unsaturated fatty acids and acetoacetate may contribute to low HDL cholesterol and increased cardiovascular risk of diabetic patients.