PT  - JOURNAL ARTICLE
AU  - Uehara, Yoshinari
AU  - Engel, Thomas
AU  - Li, Zhengchen
AU  - Goepfert, Christian
AU  - Rust, Stephan
AU  - Zhou, Xiaoqin
AU  - Langer, Claus
AU  - Schachtrup, Christian
AU  - Wiekowski, Johannes
AU  - Lorkowski, Stefan
AU  - Assmann, Gerd
AU  - von Eckardstein, Arnold
TI  - Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1
AID  - 10.2337/diabetes.51.10.2922
DP  - 2002 Oct 01
TA  - Diabetes
PG  - 2922--2928
VI  - 51
IP  - 10
4099  - http://diabetes.diabetesjournals.org/content/51/10/2922.short
4100  - http://diabetes.diabetesjournals.org/content/51/10/2922.full
SO  - Diabetes2002 Oct 01; 51
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.