HIF-1beta determines ABCA1 expression under hypoxia in human macrophages.

Abstract

ATP-binding cassette transporter A1 plays (ABCA1) a major role in reverse cholesterol transport, a process closely related to atherogenesis. In the thickening atherosclerotic lesions lipid loaded macrophages are exposed to regions of local hypoxia that may influence reverse cholesterol transport. Here we studied the effect of hypoxia on ABCA1 regulation and cholesterol efflux in human macrophages. We found that the hypoxia-inducible factor 1 (HIF-1) specifically binds to the HIF-1 response element of the ABCA1 promoter and the HIF-1 complex increases ABCA1 promoter activity along with ABCA1 expression. Primary human macrophages exposed to hypoxia or expressing constitutively active HIF-1alpha responded with a potent change in ABCA1 expression, which showed a strong correlation with HIF-1beta expression (r: 0.95-0.91). Moreover, ABCA1-mediated cholesterol efflux was also found to be regulated by HIF-1beta under hypoxia. In vivo, in macrophages prepared from human atherosclerotic lesions ABCA1 levels showed a strong correlation with HIF-1beta expression. This in vivo regulatory mechanism was confirmed in human pre-eclamptic placentas, a clinical condition with severe local hypoxia. These results demonstrate that HIF-1beta availability determines ABCA1 expression and cholesterol efflux in macrophages under hypoxia and may contribute to the interpersonal variability of atherosclerotic lesion progression.

• Authors: Peter Ugocsai, Antonia Hohenstatt, György Paragh, Gerhard Liebisch, Thomas Langmann, Zsuzsanna Wolf, Thomas Weiss, Peter Groitl, Thomas Dobner, Piotr Kasprzak, László Göbölös, Andreas Falkert, Birgit Seelbach-Goebel, Alexandra Gellhaus, Elke Winterhager, Markus Schmidt, Gregg L Semenza, Gerd Schmitz
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 42 Issue 2 Pg. 241-52 (Feb 2010) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 19828131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Chemical References

• ABCA1 protein, human
• ARNT protein, human
• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters
• Protein Isoforms
• RNA, Messenger
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Cholesterol

Topics

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adenoviridae (genetics)
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
• Atherosclerosis (metabolism, pathology)
• Binding Sites
• Cell Differentiation
• Cell Hypoxia
• Cell Line
• Cholesterol (metabolism)
• Female
• Gene Expression Regulation
• Hepatocytes (metabolism)
• Humans
• Macrophages (cytology, metabolism)
• Monocytes (cytology)
• Placenta (metabolism)
• Pre-Eclampsia (metabolism)
• Pregnancy
• Promoter Regions, Genetic (genetics)
• Protein Isoforms (metabolism)
• RNA, Messenger (genetics, metabolism)
• Reproducibility of Results
• Transcription, Genetic
• Transduction, Genetic