Journal
JOURNAL OF LIPID RESEARCH
Volume 55, Issue 6, Pages 1066-1076Publisher
ELSEVIER
DOI: 10.1194/jlr.M044925
Keywords
ATP binding cassette transporter A1; human antigen R; posttranscriptional regulation; lipid homeostasis; cholesterol efflux
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Funding
- National Institutes of Health [R01HL107953, R01HL106063, 1F31AG043318]
- American Heart Association [12POST9780016]
- Tri-Service General Hospital [TSGH-C103-027]
- National Institute on Aging-Intramural Research Program
- National Institutes of Health
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ABCA1 is a major regulator of cellular cholesterol efflux and plasma HDL biogenesis. Even though the transcriptional activation of ABCA1 is well established, the posttranscriptional regulation of ABCA1 expression is poorly understood. Here, we investigate the potential contribution of the RNA binding protein (RBP) human antigen R (HuR) on the posttranscriptional regulation of ABCA1 expression. RNA immunoprecipitation assays demonstrate a direct interaction between HuR and ABCA1 mRNA. We found that HuR binds to the 3' untranslated region of ABCA1 and increases ABCA1 translation, while HuR silencing reduces ABCA1 expression and cholesterol efflux to ApoA1 in human hepatic (Huh-7) and monocytic (THP-1) cells. Interestingly, cellular cholesterol levels regulate the expression, intracellular localization, and interaction between HuR and ABCA1 mRNA. Finally, we found that HuR expression was significantly increased in macrophages from human atherosclerotic plaques, suggesting an important role for this RBP in controlling macrophage cholesterol metabolism in vivo. In summary, we have identified HuR as a novel posttranscriptional regulator of ABCA1 expression and cellular cholesterol homeostasis, thereby opening new avenues for increasing cholesterol efflux from atherosclerotic foam macrophages and raising circulating HDL cholesterol levels.
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