Details

Autor(en) / Beteiligte

• UEHARA, Yoshinari
• ENGEL, Thomas
• ASSMANN, Gerd
• VON ECKARDSTEIN, Arnold
• ZHENGCHEN LI
• GOEPFERT, Christian
• RUST, Stephan
• XIAOQIN ZHOU
• LANGER, Claus
• SCHACHTRUP, Christian
• WIEKOWSKI, Johannes
• LORKOWSKI, Stefan

Titel

Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1

Ist Teil von

• Diabetes (New York, N.Y.), 2002-10, Vol.51 (10), p.2922-2928

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2002

Quelle

MEDLINE

Beschreibungen/Notizen

• Polyunsaturated Fatty Acids and Acetoacetate Downregulate the Expression of the ATP-Binding Cassette Transporter A1 Yoshinari Uehara 1 2 3 , Thomas Engel 2 , Zhengchen Li 2 , Christian Goepfert 1 , Stephan Rust 2 , Xiaoqin Zhou 2 , Claus Langer 2 , Christian Schachtrup 4 , Johannes Wiekowski 2 , Stefan Lorkowski 2 , Gerd Assmann 1 2 and Arnold von Eckardstein 1 2 3 1 Institute of Clinical Chemistry and Laboratory Medicine, Central Laboratory, Westphalian Wilhelms-University, Münster, Germany 2 Institute of Arteriosclerosis Research, Münster, Germany 3 University Hospital Zürich, Institute of Clinical Chemistry, Zürich, Switzerland 4 Department of Biochemistry, University of Münster, Münster, Germany Abstract 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. Footnotes Address correspondence and reprint requests to Dr. Arnold von Eckardstein, University Hospital Zürich, Institute of Clinical Chemistry, Rämistrasse 100, CH 8091 Zürich, Switzerland. E-mail: arnold.voneckardstein{at}ikc.usz.ch . Received for publication 30 April 2002 and accepted in revised form12 July 2002. 9- cis- RA, 9- cis- retinoic acid; 22R-HC, 22(R)-hydroxycholesterol; ABCA1, ATP-binding cassette transporter A1; DMEM, Dulbecco’s modified Eagle’s medium; EPA, eicosapentaenoic acid; LXRα, liver-X-receptor α; IFNγ, interferon-γ; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; RXRα, retinoid-X-receptor α. DIABETES