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Overexpression of A-kinase anchoring protein 12A activates sterol regulatory element binding protein-2 and enhances cholesterol efflux in hepatic cells

Cited 4 time in Web of Science Cited 4 time in Scopus
Authors
Choi, Moon-Chang; Lee, Yang-Ui; Kim, Sung-Hak; Lee, Ju-Hee; Park, Jung-Hyun; Streb, Jeffrey W; Oh, Do-Youn; Im, Seock-Ah; Kim, Tae-You; Jong, Hyun-Soon; Bang, Yung-Jue
Issue Date
2008-06-27
Publisher
Elsevier
Citation
Int J Biochem Cell Biol. 2008;40(11):2534-2543
Keywords
A Kinase Anchor Proteins/genetics/*metabolismCell Cycle Proteins/genetics/*metabolismCell LineCholesterol/*metabolismHepatocytes/cytology/*physiologyHumansIntracellular Signaling Peptides and Proteins/genetics/metabolismMembrane Proteins/genetics/metabolismMicroarray AnalysisRNA InterferenceRecombinant Fusion Proteins/genetics/metabolismSignal Transduction/*physiologySterol Regulatory Element Binding Protein 2/genetics/*metabolism
Abstract
A-kinase anchoring protein 12 (AKAP12) is known to function as a scaffold protein and as a putative tumor suppressor. However, little is known about the biological role of AKAP12 in hepatic cells. In this study, we performed micro-array analysis to identify the downstream pathway of AKAP12A, and found that AKAP12A overexpression up-regulates the expressions of several cholesterol-associated genes including HMG-CoA reductase and LDL receptor, which have been reported to be controlled by sterol regulatory element binding protein-2 (SREBP-2). It was found that AKAP12A activates SREBP-2 in hepatic cells, as demonstrated by the presence of its cleavage product, whereas the activation of sterol regulatory element binding protein-1 was not remarkably changed. Moreover, AKAP12A-induced SREBP-2 activation was found to depend on SREBP cleavage-activating protein (SCAP), as inhibition of SCAP by RNAi or sterols blocked SREBP-2 activation in response to AKAP12A overexpression. Interestingly, the hydrophobic amine U18666A caused dramatic movement of AKAP12A from the plasma membrane to cytosol and lysosomal membranes. Moreover, cholesterol depletion from the plasma membrane (using methyl-beta-cyclodextrin) caused a shift of AKAP12A from the plasma membrane to the cytoplasm. Cholesterol binding assay revealed that the N-terminal region of AKAP12A binds directly to cholesterol in vitro. Furthermore, AKAP12A overexpression enhanced [3H]-cholesterol efflux to extracellular acceptors, suggesting that AKAP12A may activate SREBP-2 by increasing cholesterol efflux. In conclusion, the present study suggests that AKAP12A is a novel regulator of cellular cholesterol metabolism.
ISSN
1357-2725 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18579430

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TCH-4SJG6D0-1-X&_cdi=5171&_user=168665&_orig=search&_coverDate=12%2F31%2F2008&_sk=999599988&view=c&wchp=dGLbVtz-zSkWA&md5=e4537f897123191f4c86c8de6e89258d&ie=/sdarticle.pdf

http://hdl.handle.net/10371/68174
DOI
https://doi.org/10.1016/j.biocel.2008.04.020
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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