title: RNA binding protein HuR regulates the expression of ABCA1.
abstract: 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 circulat-ing HDL cholesterol levels.
authors.affiliation: Vascular Biology and Therapeutics Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520 Departments of Medicine and Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Departments of Medicine and Cell Biology, New York University School of Medicine, New York, NY 10016 Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Chin Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.affiliation: Vascular Biology and Therapeutics Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520 Departments of Medicine and Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors.forename: Je-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Departments of Medicine and Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Vascular Research Lab, IIS-Fundación Jimenez Díaz, Autónoma University, Madrid 28040, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martin-Ventura
authors.affiliation: Children's Cancer Research Institute, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
authors.forename: Dat T
authors.initials: DT
authors.lastname: Vo
authors.affiliation: Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Uren
authors.affiliation: Children's Cancer Research Institute, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
authors.forename: Luiz O
authors.initials: LO
authors.lastname: Penalva
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Vascular Biology and Therapeutics Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520 Departments of Medicine and Cell Biology, New York University School of Medicine, New York, NY 10016.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000074084:THP-1 Cells
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D002784:Cholesterol
keywords: ATP binding cassette transporter A1; cholesterol efflux; human antigen R; lipid homeostasis; posttranscriptional regulation
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