HIF-1beta determines ABCA1 expression under hypoxia in human macrophages.
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.
Ugocsai
Peter
P
Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
Hohenstatt
Antonia
A
Paragh
György
G
Liebisch
Gerhard
G
Langmann
Thomas
T
Wolf
Zsuzsanna
Z
Weiss
Thomas
T
Groitl
Peter
P
Dobner
Thomas
T
Kasprzak
Piotr
P
Göbölös
László
L
Falkert
Andreas
A
Seelbach-Goebel
Birgit
B
Gellhaus
Alexandra
A
Winterhager
Elke
E
Schmidt
Markus
M
Semenza
Gregg L
GL
Schmitz
Gerd
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D014161:Transduction, Genetic
C577836:ABCA1 protein, human; C497396:ARNT protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D020033:Protein Isoforms; D012333:RNA, Messenger; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002784:Cholesterol